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Panahizadeh R, Panahi P, Asghariazar V, Makaremi S, Noorkhajavi G, Safarzadeh E. A literature review of recent advances in gastric cancer treatment: exploring the cross-talk between targeted therapies. Cancer Cell Int 2025; 25:23. [PMID: 39856676 PMCID: PMC11762578 DOI: 10.1186/s12935-025-03655-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2024] [Accepted: 01/17/2025] [Indexed: 01/27/2025] Open
Abstract
BACKGROUND Gastric cancer (GC) ranks fourth in global mortality rates and fifth in prevalence, making it one of the most common cancers worldwide. Recent clinical studies have highlighted the potential of immunotherapies as a promising approach to treating GC. This study aims to shed light on the most impactful therapeutic strategies in the context of GC immunotherapy, highlighting both established and emerging approaches. MAIN BODY This review examines over 160 clinical studies conducted globally, focusing on the effectiveness of various immunotherapy modalities, including cancer vaccines, adoptive cell therapy, immune checkpoint inhibitors (ICIs), and monoclonal antibodies (mAbs). A comprehensive search of peer-reviewed literature was performed using databases such as Web of Science, PubMed, and Scopus. The selection criteria included peer-reviewed articles published primarily within the last 10 years, with a focus on studies that provided insights into targeted therapies and their mechanisms of action, clinical efficacy, and safety profiles. The findings indicate that these immunotherapy strategies can enhance treatment outcomes for GC, aligning with current treatment guidelines. ICIs like pembrolizumab and nivolumab have shown significant survival benefits in specific GC subgroups. Cancer vaccines and CAR-T cell therapies demonstrate potential, while mAbs targeting HER2 and VEGFR pathways enhance outcomes in combination regimens. We discuss the latest advancements and challenges in targeted therapy and immunotherapy for GC. Given the evolving nature of this field, this research emphasizes significant evidence-based therapies and those currently under evaluation rather than providing an exhaustive overview. Challenges include resistance mechanisms, immunosuppressive tumor environments, and inconsistent results from combination therapies. Biomarker-driven approaches and further research into emerging modalities like CAR-T cells and cancer vaccines are critical for optimizing treatments. CONCLUSIONS Immunotherapy is reshaping GC management by improving survival and quality of life. Ongoing research and clinical evaluations are crucial for refining personalized and effective therapies.
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Affiliation(s)
- Reza Panahizadeh
- Cancer Immunology and Immunotherapy Research Center, Ardabil University of Medical Sciences, Ardabil, Iran
- Students Research Committee, School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Padideh Panahi
- Student Research Committee, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Vahid Asghariazar
- Cancer Immunology and Immunotherapy Research Center, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Shima Makaremi
- Cancer Immunology and Immunotherapy Research Center, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Ghasem Noorkhajavi
- Cancer Immunology and Immunotherapy Research Center, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Elham Safarzadeh
- Cancer Immunology and Immunotherapy Research Center, Ardabil University of Medical Sciences, Ardabil, Iran.
- Department of Microbiology, Parasitology and Immunology, School of Medicine, Ardabil University of Medical Sciences, Ardabil, 85991-56189, Iran.
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Lakhani NJ, Stewart D, Richardson DL, Dockery LE, Van Le L, Call J, Rangwala F, Wang G, Ma B, Metenou S, Huguet J, Offman E, Pandite L, Hamilton E. First-in-human phase I trial of the bispecific CD47 inhibitor and CD40 agonist Fc-fusion protein, SL-172154 in patients with platinum-resistant ovarian cancer. J Immunother Cancer 2025; 13:e010565. [PMID: 39800375 PMCID: PMC11749819 DOI: 10.1136/jitc-2024-010565] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Accepted: 12/18/2024] [Indexed: 01/23/2025] Open
Abstract
BACKGROUND SL-172154 is a hexameric fusion protein adjoining the extracellular domain of SIRPα to the extracellular domain of CD40L via an inert IgG4-derived Fc domain. In preclinical studies, a murine equivalent SIRPα-Fc-CD40L fusion protein provided superior antitumor immunity in comparison to CD47- and CD40-targeted antibodies. A first-in-human phase I trial of SL-172154 was conducted in patients with platinum-resistant ovarian cancer. METHODS SL-172154 was administered intravenously at 0.1, 0.3, 1.0, 3.0, and 10.0 mg/kg. Dose escalation followed a modified toxicity probability interval-2 design. Objectives included evaluation of safety, dose-limiting toxicity, recommended phase II dose, pharmacokinetic (PK) and pharmacodynamic (PD) parameters, and antitumor activity. RESULTS 27 patients (median age 66 years (range, 33-85); median of 4 prior systemic therapies (range, 2-9)) with ovarian (70%), fallopian tube (15%), or primary peritoneal (15%) cancer received SL-172154. Treatment-emergent adverse events (TEAEs) were reported for 27 patients (100%), with 24 (88.9%) having a drug-related TEAE and infusion-related reactions being the most common. 12 patients (44.4%) had grade 3/4 TEAEs, and half of these patients (22.2%) had a drug-related grade 3/4 TEAE. There were no fatal adverse events, and no TEAEs led to drug discontinuation. SL-172154 Cmax and area under the curve increased with dose with greater than proportional exposure noted at 3.0 and 10.0 mg/kg. CD47 and CD40 target engagement on CD4+ T cells and B cells, respectively, approached 100% by 3.0 mg/kg. Dose-dependent responses in multiple cytokines (eg, interleukin 12 (IL-12), IP-10) approached a plateau at ≥3.0 mg/kg. Paired tumor biopsies demonstrated a shift in macrophages from an M2- to an M1-dominant phenotype and increased infiltration of CD8 T cells. PK/PD modeling showed near maximal margination of B cells and a dose-dependent production of IL-12 nearing a plateau at >3.0 mg/kg. The best response was stable disease in 6/27 (22%) patients. CONCLUSIONS SL-172154 was tolerable as monotherapy and induced, dose-dependent, and cyclical immune cell activation, increases in multiple serum cytokines, and trafficking of CD40-positive B cells and monocytes following each infusion. The safety, PK, and PD activity support 3.0 mg/kg as a safe and pharmacologically active dose. TRIAL REGISTRATION NUMBER NCT04406623.
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Affiliation(s)
- Nehal J Lakhani
- Clinical Research, START Midwest, Grand Rapids, Michigan, USA
| | - Daphne Stewart
- Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, California, USA
| | - Debra L Richardson
- Division of Gynecologic Oncology, Stephenson Cancer Center and Sarah Cannon Research Institute/University of Oklahoma, Oklahoma City, Oklahoma, USA
| | - Lauren E Dockery
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA
| | - Linda Van Le
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA
| | - Justin Call
- Medical Oncology, START Mountain Region, West Valley City, Utah, USA
| | - Fatima Rangwala
- Clinical Research, Shattuck Labs R&D Office, Durham, North Carolina, USA
| | - Guanfang Wang
- Biometrics, Shattuck Labs R&D Office, Durham, North Carolina, USA
| | - Bo Ma
- Biometrics, Shattuck Labs R&D Office, Durham, North Carolina, USA
| | - Simon Metenou
- Translational Medicine, Shattuck Labs R&D Office, Durham, North Carolina, USA
| | - Jade Huguet
- Translational and Clinical Pharmacology, Certara, Toronto, Ontario, Canada
| | - Elliot Offman
- Translational and Clinical Pharmacology, Certara, Toronto, Ontario, Canada
| | - Lini Pandite
- Clinical Research, Shattuck Labs R&D Office, Durham, North Carolina, USA
| | - Erika Hamilton
- Medical Oncology, Sarah Cannon Research Institute, Nashville, Tennessee, USA
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Nakabayashi Y, Kiuchi J, Kubota T, Ohashi T, Nishibeppu K, Imamura T, Nanishi K, Shimizu H, Arita T, Yamamoto Y, Konishi H, Morimura R, Komatsu S, Shiozaki A, Ikoma H, Kuriu Y, Fujiwara H, Tsuda H, Otsuji E. A novel semi-quantitative scoring method for CD8+ tumor-infiltrating lymphocytes based on infiltration sites in gastric cancer. Am J Cancer Res 2024; 14:5965-5986. [PMID: 39803654 PMCID: PMC11711524 DOI: 10.62347/jkcu5881] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Accepted: 12/18/2024] [Indexed: 01/16/2025] Open
Abstract
No established method currently exists for evaluating tumor-infiltrating lymphocytes (TILs) in gastric cancer (GC), and their clinical significance based on infiltration site in GC remains unclear. In this study, we developed a method to evaluate TILs according to their infiltration site as a prognostic marker for GC. We retrospectively analyzed 103 patients with advanced GC who underwent curative resection. TILs located at the invasive margin (TILIM) and the center of tumors (TILCT) were scored semi-quantitatively using immunohistochemical staining of CD8+ T cells. The sum of the TILIM and TILCT scores was defined as the TILs score. Based on this score, patients were classified into low and high TILs groups. Quantitative TILs were also assessed to validate the semi-quantitative scoring method. Furthermore, we confirmed a tumor suppressive effect due to CD8+ T cells co-cultured in GC cell lines in vitro. In the univariate analysis, patients with low TILIM were significantly more likely to be female, younger, and have undifferentiated histological types and deeper tumor invasion compared to those with high TILIM. Similarly, patients with low TILCT had significantly more positive lymph node metastases than those with high TILCT. In the multivariate analysis, deeper tumor invasion and positive lymph node metastasis were identified as independent risk factors for patients with low TILIM and low TILCT, respectively. According to our semi-quantitative TILs scoring method, the low TILs group had significantly poorer prognoses compared to the high TILs group. This group had significantly larger tumor diameters, deeper tumor invasion, and more positive lymph node metastases. Additionally, deeper tumor invasion was an independent risk factor for the low TILs group. Quantitative TILs analysis revealed that the low TILs group had significantly lower TIL levels compared to the high TILs group. In vitro, CD8+ T cells induced apoptosis in GC cells in a concentration-dependent manner. Furthermore, these cells significantly suppressed the proliferative, migratory, and invasive capacities of GC cells. Our simple and versatile semi-quantitative scoring method for CD8+ TILs indicates that CD8+ TILs are sensitive prognostic markers. The low TILs group accurately reflects the low quantitative TIL levels and is associated with poor oncological prognosis.
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Affiliation(s)
- Yudai Nakabayashi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of MedicineKawaramachi-Hirokoji, Kamigyo-ku, Kyoto, Japan
| | - Jun Kiuchi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of MedicineKawaramachi-Hirokoji, Kamigyo-ku, Kyoto, Japan
| | - Takeshi Kubota
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of MedicineKawaramachi-Hirokoji, Kamigyo-ku, Kyoto, Japan
| | - Takuma Ohashi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of MedicineKawaramachi-Hirokoji, Kamigyo-ku, Kyoto, Japan
| | - Keiji Nishibeppu
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of MedicineKawaramachi-Hirokoji, Kamigyo-ku, Kyoto, Japan
| | - Taisuke Imamura
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of MedicineKawaramachi-Hirokoji, Kamigyo-ku, Kyoto, Japan
| | - Kenji Nanishi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of MedicineKawaramachi-Hirokoji, Kamigyo-ku, Kyoto, Japan
| | - Hiroki Shimizu
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of MedicineKawaramachi-Hirokoji, Kamigyo-ku, Kyoto, Japan
| | - Tomohiro Arita
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of MedicineKawaramachi-Hirokoji, Kamigyo-ku, Kyoto, Japan
| | - Yusuke Yamamoto
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of MedicineKawaramachi-Hirokoji, Kamigyo-ku, Kyoto, Japan
| | - Hirotaka Konishi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of MedicineKawaramachi-Hirokoji, Kamigyo-ku, Kyoto, Japan
| | - Ryo Morimura
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of MedicineKawaramachi-Hirokoji, Kamigyo-ku, Kyoto, Japan
| | - Shuhei Komatsu
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of MedicineKawaramachi-Hirokoji, Kamigyo-ku, Kyoto, Japan
| | - Atsushi Shiozaki
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of MedicineKawaramachi-Hirokoji, Kamigyo-ku, Kyoto, Japan
| | - Hisashi Ikoma
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of MedicineKawaramachi-Hirokoji, Kamigyo-ku, Kyoto, Japan
| | - Yoshiaki Kuriu
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of MedicineKawaramachi-Hirokoji, Kamigyo-ku, Kyoto, Japan
| | - Hitoshi Fujiwara
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of MedicineKawaramachi-Hirokoji, Kamigyo-ku, Kyoto, Japan
| | - Hitoshi Tsuda
- Department of Basic Pathology, National Defense Medical CollegeTokorozawa, Japan
| | - Eigo Otsuji
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of MedicineKawaramachi-Hirokoji, Kamigyo-ku, Kyoto, Japan
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Shahi A, Kidane D. Aberrant DNA polymerase beta expression is associated with dysregulated tumor immune microenvironment and its prognostic value in gastric cancer. Clin Exp Med 2024; 24:239. [PMID: 39402431 PMCID: PMC11473650 DOI: 10.1007/s10238-024-01498-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Accepted: 09/24/2024] [Indexed: 10/19/2024]
Abstract
BACKGROUND Gastric cancer is caused by different exogenous risk factors. Polymerase beta (POLB) is critical to repair oxidative and alkylating-induced DNA damage in genome maintenance. It is unknown whether overexpression of POLB genes in GC modulates tumor immunogenicity and plays a role in its prognostic value. METHODS RNA-Seq of GC data retrieved from TCGA and GEO database and patient survival were compared using Kaplan-Meier statistical test. The TIMER algorithm was used to calculate the abundance of tumor-infiltrating immune cells. Furthermore, ROC analysis was applied to evaluate the prognostic value of POLB overexpression. RESULTS Our data analysis of TCGA and GEO gastric cancer genomics datasets reveals that POLB overexpression is significantly associated with intestinal subtypes of stomach cancer. In addition, POLB overexpression is associated with low expression of innate immune signaling genes. In contrast, POLB-overexpressed tumor harbors high mutation frequency and MSI score. Furthermore, POLB-overexpressed tumor with high immune score exhibits a better prognosis. Interestingly, our ROC analysis results suggested that POLB overexpression has a potential for prognostic markers for stomach cancer. CONCLUSIONS Our analysis suggests that aberrant POLB overexpression in stomach cancer impacts the diverse aspects of tumor immune microenvironment. In addition, POLB might be a potential prognosis marker and/or an attractive target for immune-based therapy in GC. However, our observation still requires further experimental-based scientific validation studies.
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Affiliation(s)
- Aashirwad Shahi
- Department of Physiology & Biophysics, College of Medicine, Howard University, 520 W Street NW, Washington, DC, 20059, USA
| | - Dawit Kidane
- Department of Physiology & Biophysics, College of Medicine, Howard University, 520 W Street NW, Washington, DC, 20059, USA.
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Dong H, Yao L, Fan J, Gao P, Yang X, Yuan Z, Zhang T, Lu M, Chen X, Suo C. Characteristics of auto-quantified tumor-infiltrating lymphocytes and the prognostic value in adenocarcinoma of the esophagogastric junction, gastric adenocarcinoma, and esophageal squamous cell carcinoma. Aging (Albany NY) 2024; 16:11027-11061. [PMID: 38975889 PMCID: PMC11272125 DOI: 10.18632/aging.205999] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Accepted: 06/10/2024] [Indexed: 07/09/2024]
Abstract
BACKGROUND Adenocarcinoma of the esophagogastric junction (AEGJ) with a specific pathological profile and poor prognosis has limited therapeutic options. Previous studies have found that TILs exhibit distinct characteristics in different tumors and are correlated with tumor prognosis. We established cellular training sets to obtain auto-quantified TILs in pathological images. And we compared the characteristics of TILs in AEGJ with those in esophageal squamous cell carcinoma (ESCC) and gastric adenocarcinoma (GAC) to gain insight into the unique immune environments of these three tumors and investigate the prognostic value of TILs in these three tumors. METHODS Utilizing a case-control study design, we analyzed 214 AEGJ, 256 GAC, and 752 ESCC cases. The TCGA dataset was used to validate prognostic value of auto-quantified TILs. The specific cellular training sets were established by experienced pathologists to determine TILs counts. Kruskal-Wallis test and multi-variable linear regression were conducted to explore TILs characteristics. Survival analyses were performed with Kaplan-Meier method and Cox proportional hazards model. RESULTS The three cellular training sets of these cancers achieved a classification accuracy of 87.55 at least. The median auto-quantified TILs of AEGJ, GAC, and ESCC cases were 4.82%, 1.92%, and 0.12%, respectively. The TILs demonstrated varied characteristics under distinctive clinicopathological traits. The higher TILs proportion was associated with better prognosis in esophagogastric cancers (all P < 0.05) and was an independent prognostic biomarker on AEGJ in both datasets (Taixing: HR = 0.965, 95% CI = 0.938-0.994; TCGA: HR = 0.811, 95% CI = 0.712-0.925). CONCLUSIONS We found variations in TILs across ESCC, GAC, and AEGJ, as assessed by image processing algorithms. Additionally, TILs in these three cancers are an independent prognostic factor. This enhances our understanding of the unique immune characteristics of the three tumors, improving patient outcomes.
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Affiliation(s)
- Hao Dong
- Department of Epidemiology and Ministry of Education Key Laboratory of Public Health Safety, School of Public Health, Fudan University, Shanghai, China
| | - Longqing Yao
- State Key Laboratory of Genetic Engineering, Human Phenome Institute, School of Life Sciences, Fudan University, Shanghai, China
| | - Jiahui Fan
- Department of Clinical Laboratory, Shanghai Fourth People’s Hospital Affiliated to Tongji University School of Medicine, Shanghai, China
| | - Peipei Gao
- State Key Laboratory of Genetic Engineering, Human Phenome Institute, School of Life Sciences, Fudan University, Shanghai, China
- Fudan University Taizhou Institute of Health Sciences, Taizhou, China
| | - Xiaorong Yang
- Fudan University Taizhou Institute of Health Sciences, Taizhou, China
- Clinical Epidemiology Unit, Qilu Hospital of Shandong University, Jinan, China
| | - Ziyu Yuan
- Fudan University Taizhou Institute of Health Sciences, Taizhou, China
| | - Tiejun Zhang
- Department of Epidemiology and Ministry of Education Key Laboratory of Public Health Safety, School of Public Health, Fudan University, Shanghai, China
- Fudan University Taizhou Institute of Health Sciences, Taizhou, China
| | - Ming Lu
- Fudan University Taizhou Institute of Health Sciences, Taizhou, China
- Clinical Epidemiology Unit, Qilu Hospital of Shandong University, Jinan, China
| | - Xingdong Chen
- State Key Laboratory of Genetic Engineering, Human Phenome Institute, School of Life Sciences, Fudan University, Shanghai, China
- Fudan University Taizhou Institute of Health Sciences, Taizhou, China
- Yiwu Research Institute of Fudan University, Yiwu, Zhejiang, China
| | - Chen Suo
- Department of Epidemiology and Ministry of Education Key Laboratory of Public Health Safety, School of Public Health, Fudan University, Shanghai, China
- Fudan University Taizhou Institute of Health Sciences, Taizhou, China
- Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai, China
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Lin J, Huang C, Diao W, Liu H, Lu H, Huang S, Wang J. CPE correlates with poor prognosis in gastric cancer by promoting tumourigenesis. Heliyon 2024; 10:e29901. [PMID: 38694095 PMCID: PMC11058891 DOI: 10.1016/j.heliyon.2024.e29901] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 04/16/2024] [Accepted: 04/17/2024] [Indexed: 05/03/2024] Open
Abstract
Aims To investigate the potential functions and mechanisms of tumourigenesis in carboxypeptidase E (CPE) and its prognostic value in gastric cancer, and to develop a predictive model for prognosis based on CPE. Results Transcriptome level variation and the prognostic value of CPE in different types of cancers were investigated using bioinformatics analyses. The association between CPE and clinicopathological characteristics was specifically explored in gastric cancer. Elevated CPE expression was associated with poor survival and recurrence prognosis and was found in cases with a later clinical stage of gastric cancer. The CPE was considered an independent prognostic factor, as assessed using Cox regression analysis. The prognostic value of CPE was further verified through immunohistochemistry and haematoxylin staining. Enrichment analysis provided a preliminary confirmation of the potential functions and mechanisms of CPE. Immune cell infiltration analysis revealed a significant correlation between CPE and macrophage infiltration. Eventually, a prognosis prediction nomogram model based on CPE was developed. Conclusion CPE was identified as an independent biomarker associated with poor prognosis in gastric cancer. This suggests that CPE overexpression promoted epithelial-mesenchymal transition via the activation of the Erk/Wnt pathways, leading to proliferation, invasion, and metastasis. Targeted therapeutic strategies for gastric cancer may benefit from these findings.
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Affiliation(s)
- Jiarui Lin
- Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, China
| | - Chengzhi Huang
- Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, China
- Department of General Surgery, Guangdong Provincial People's Hospital Ganzhou Hospital (Ganzhou Municipal Hospital), Ganzhou, 341000, China
- School of Medicine, South China University of Technology, Guangzhou, 510006, China
| | - Wenfei Diao
- Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, China
- Shantou University Medical College, Shantou, 515000, China
| | - Haoming Liu
- Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, China
| | - Hesong Lu
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, 510080, China
| | - Shengchao Huang
- Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, China
| | - Junjiang Wang
- Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, China
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Li D, Huang P, Xia L, Leng W, Qin S. Cancer-associated fibroblasts promote gastric cancer cell proliferation by paracrine FGF2-driven ribosome biogenesis. Int Immunopharmacol 2024; 131:111836. [PMID: 38479160 DOI: 10.1016/j.intimp.2024.111836] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2024] [Revised: 03/05/2024] [Accepted: 03/08/2024] [Indexed: 04/10/2024]
Abstract
The cancer-associated fibroblast (CAF)-derived secretome plays critical roles in tumor progression by remodelling tumor microenvironment. Tumorigenesis is accompanied by the transformation of normal fibroblasts (NF) into CAF, leading to significant changes in their secretome. This work aims to identify the differential components of secretome between NFs and CAFs and reveal their functions in gastric cancer (GC). Firstly, our molecular typing studies and immune infiltration analysis showed that CAF infiltration level was increased and showed a significant association with clinical characteristics and poor prognosis of GC patients. Secondly, RNA-seq analysis revealed that a total of 1531 genes showed significant expression changes between NF and CAF. According to the annotation of the Human Protein Atlas (HPA) database, 147 genes encode secreted proteins, including FGF2. Particularly, the cell co-culture and RNA sequencing studies confirmed that exogenous recombinant FGF2 protein treatment promoted GC cell proliferation by enhancing ribosome biogenesis. The rescue assay showed that CAF-secreted FGF2 protein promotes GC cell growth and proliferation in a FGFR1-dependent manner. Our finding provides evidence that targeting blockade of CAF-derived FGF2 protein might be a promising treatment for GC.
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Affiliation(s)
- Dandan Li
- Department of Stomatology, Taihe Hospital and Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, Hubei 442000, China; Laboratory of Tumor Biology, Academy of Bio-Medicine Research, Hubei University of Medicine, Shiyan, Hubei 442000, China; Shiyan Key Laboratory of Natural Medicine Nanoformulation Research, Hubei University of Medicine, Shiyan, Hubei 442000, China
| | - Pan Huang
- Department of Stomatology, Taihe Hospital and Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, Hubei 442000, China; Laboratory of Tumor Biology, Academy of Bio-Medicine Research, Hubei University of Medicine, Shiyan, Hubei 442000, China
| | - Lingyun Xia
- Department of Stomatology, Taihe Hospital and Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, Hubei 442000, China
| | - Weidong Leng
- Department of Stomatology, Taihe Hospital and Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, Hubei 442000, China.
| | - Shanshan Qin
- Department of Stomatology, Taihe Hospital and Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, Hubei 442000, China; Laboratory of Tumor Biology, Academy of Bio-Medicine Research, Hubei University of Medicine, Shiyan, Hubei 442000, China; Shiyan Key Laboratory of Natural Medicine Nanoformulation Research, Hubei University of Medicine, Shiyan, Hubei 442000, China.
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Kobayashi G, Imai T, Sentani K. Distribution and Clinicopathological Features of Mott Cells (Plasma Cells Containing Russell Bodies) in Gastric Cancer: Presence of Mott Cells Is Associated with Favorable Prognosis. J Clin Med 2024; 13:658. [PMID: 38337351 PMCID: PMC10856670 DOI: 10.3390/jcm13030658] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Revised: 01/15/2024] [Accepted: 01/19/2024] [Indexed: 02/12/2024] Open
Abstract
Gastric cancer (GC) is still one of the leading causes of cancer-related mortality. We previously reported the relationship between histological heterogeneity of tumor cells and molecular features in GC. The tumor microenvironment also has a crucial role in GC progression and therapeutic resistance. In this study, we focused on the tumor microenvironment, especially inflammatory cells in GC. Using GC tissue slides, we investigated the distribution and clinicopathological significance of inflammatory cell counts including eosinophils, neutrophils, lymphocytes, and plasma cells. Additionally, we investigated the relationship between Mott cells (plasma cells containing Russell bodies) and clinicopathological features. In neoplastic gastric mucosa, a high number of plasma cells was associated with low T-grade, early stage, and good prognosis. We then focused on Mott cells and found that their presence in neoplastic gastric mucosa was associated with lower T and N grades, early stage, and Helicobacter pylori infection and was inversely associated with CD44 and EGFR expression. Additionally, the presence of Mott cells was associated with good prognosis in advanced GC and was an independent favorable prognostic predictor. The presence of Mott cells in GC might be one useful prognostic predictor, and Mott cells might have an important role in the carcinogenesis of H. pylori infection.
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Affiliation(s)
- Go Kobayashi
- Laboratory of Molecular Pathology, Department of Molecular Biosciences, Radiation Effects Research Foundation, Hiroshima 732-0815, Japan;
- Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan
| | - Takeharu Imai
- Department of Surgical Oncology, Graduate School of Medicine Gifu University, Gifu 501-1194, Japan;
| | - Kazuhiro Sentani
- Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan
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Shi X, Li S, Wang Y, Liu C, Liu P, Qin D. Predictive value of platelet-to-lymphocyte ratio combined with CA199 levels in postoperative survival of patients with gastric cancer: A retrospective study. Int Immunopharmacol 2023; 124:110987. [PMID: 37806105 DOI: 10.1016/j.intimp.2023.110987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 09/19/2023] [Accepted: 09/22/2023] [Indexed: 10/10/2023]
Abstract
OBJECTIVE To develop a new scoring system based on platelet-to-lymphocyte ratio (PLR) and CA199 to predict the prognosis of gastric cancer. METHODS PLR-CA199 was identified in a retrospective study that was conducted in a training cohort of 990 gastric cancer patients who underwent curable resection from 2012 to 2014 and validated in a validation cohort of 625 patients between 2015 and 2016. RESULTS In the training cohort, PLR-CA199 was related to gender (P = 0.041), age (P = 0.014), tumor location (P = 0.015), tumor size (P < 0.001), Bormann type (P < 0.001), vascular invasion (P < 0.001), perineural invasion (P < 0.001), and TNM staging (P < 0.001). In the validation cohort, PLR-CA199 was related to tumor size (P < 0.001), Bormann type (P = 0.007), vascular invasion (P < 0.001), perineural invasion (P < 0.001), and TNM staging (P < 0.001). Survival analysis showed that in the training cohort the mean disease-free survival (DFS) was 70.699 months for patients PLR-CA199 = 0, 51.223 months for patients PLR-CA199 = 1, and 32.152 months for patients PLR-CA199 = 2 (P < 0.001). The correlation between PLR-CA199 and DFS was further confirmed in the validation cohort (50.640 vs. 41.842 vs. 22.382, P < 0.001). Survival analysis showed that the mean disease special survival (DSS) was 76.668 months for patients PLR-CA199 = 0, 61.218 months for patients PLR-CA199 = 1, and 44.665 months for patients PLR-CA199 = 2 in the training cohort (P < 0.001). The correlation between PLR-CA199 and DSS was further confirmed in the validation cohort (53.858 vs. 46.385 vs. 44.665, P < 0.001). Furthermore, univariate and multivariate analyses showed that PLR-CA199 was an independent prognostic factor for DFS and DSS. CONCLUSIONS Preoperative PLR-CA199 may be a useful prognostic indicator, and is a promising tool for predicting the prognosis for gastric cancer.
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Affiliation(s)
- Xiaoqing Shi
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Key Laboratory of Laboratory Medicine of Henan Province, Zhengzhou, Henan, China
| | - Sen Li
- Department of General Surgery, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, Henan, China
| | - Yuanyuan Wang
- Department of Thyroid Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Chuang Liu
- Extracorporeal Life Support Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Peipei Liu
- Clinical Systems Biology Laboratories, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Dongchun Qin
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Key Laboratory of Laboratory Medicine of Henan Province, Zhengzhou, Henan, China.
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10
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Danilova NV, Mikhailov IA, Khomyakov VM, Chaika AV, Polushkina TV, Sotnikova TN, Oleinikova NA, Mal'kov PG. Automated Assessment of the Area of Infiltration by CD8 + Cells in Gastric Carcinoma and Areas of Normal Mucosa as a Significant Prognostic Factor. Bull Exp Biol Med 2023; 175:508-512. [PMID: 37768461 DOI: 10.1007/s10517-023-05896-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Indexed: 09/29/2023]
Abstract
In 139 patients with verified gastric cancer, the infiltration of the postoperative material with CD8+ cells was analyzed. Automated morphometric analysis of immunostained slides was performed separately in different specimen sites (tumor center, invasive edge, and peritumoral mucosa). The mean area of infiltrating CD8+ cells in the tumor center and in the invasive edge was not predictive, while in the peritumoral mucosa it provided a new negative predictive factor (hazard ratio 2.10; confidence interval 0.87-4.92, Cox regression) reliably associated with the TNM stage (hazard ratio 1.91; confidence interval 0.91-4.61, Cox regression).
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Affiliation(s)
- N V Danilova
- Medical Scientific Educational Center, M. V. Lomonosov Moscow State University, Moscow, Russia.
| | - I A Mikhailov
- Medical Scientific Educational Center, M. V. Lomonosov Moscow State University, Moscow, Russia
| | - V M Khomyakov
- P. A. Herzen Moscow Research Oncological Institute - Branch of National Medical Research Center of Radiology, Ministry of Health of the Russian Federation, Moscow, Russia
| | - A V Chaika
- P. A. Herzen Moscow Research Oncological Institute - Branch of National Medical Research Center of Radiology, Ministry of Health of the Russian Federation, Moscow, Russia
| | - T V Polushkina
- I. V. Davydovsky City Clinical Hospital, Moscow Healthcare Department, Moscow, Russia
| | - T N Sotnikova
- I. V. Davydovsky City Clinical Hospital, Moscow Healthcare Department, Moscow, Russia
| | - N A Oleinikova
- Medical Scientific Educational Center, M. V. Lomonosov Moscow State University, Moscow, Russia
| | - P G Mal'kov
- Medical Scientific Educational Center, M. V. Lomonosov Moscow State University, Moscow, Russia
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11
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Yin LK, Yuan HY, Liu JJ, Xu XL, Wang W, Bai XY, Wang P. Identification of survival-associated biomarkers based on three datasets by bioinformatics analysis in gastric cancer. World J Clin Cases 2023; 11:4763-4787. [PMID: 37584004 PMCID: PMC10424043 DOI: 10.12998/wjcc.v11.i20.4763] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 04/11/2023] [Accepted: 06/06/2023] [Indexed: 07/06/2023] Open
Abstract
BACKGROUND Gastric cancer (GC) is one of the most common malignant tumors with poor prognosis in terms of advanced stage. However, the survival-associated biomarkers for GC remains unclear. AIM To investigate the potential biomarkers of the prognosis of patients with GC, so as to provide new methods and strategies for the treatment of GC. METHODS RNA sequencing data from The Cancer Genome Atlas (TCGA) database of STAD tumors, and microarray data from Gene Expression Omnibus (GEO) database (GSE19826, GSE79973 and GSE29998) were obtained. The differentially expressed genes (DEGs) between GC patients and health people were picked out using R software (x64 4.1.3). The intersections were underwent between the above obtained co-expression of differential genes (co-DEGs) and the DEGs of GC from Gene Expression Profiling Interactive Analysis database, and Gene Ontology (GO) analysis, Kyoto Encyclopedia of Gene and Genome (KEGG) pathway analysis, Gene Set Enrichment Analysis (GSEA), Protein-protein Interaction (PPI) analysis and Kaplan-Meier Plotter survival analysis were performed on these DEGs. Using Immunohistochemistry (IHC) database of Human Protein Atlas (HPA), we verified the candidate Hub genes. RESULTS With DEGs analysis, there were 334 co-DEGs, including 133 up-regulated genes and 201 down-regulated genes. GO enrichment analysis showed that the co-DEGs were involved in biological process, cell composition and molecular function pathways. KEGG enrichment analysis suggested the co-DEGs pathways were mainly enriched in ECM-receptor interaction, protein digestion and absorption pathways, etc. GSEA pathway analysis showed that co-DEGs mainly concentrated in cell cycle progression, mitotic cell cycle and cell cycle pathways, etc. PPI analysis showed 84 nodes and 654 edges for the co-DEGs. The survival analysis illustrated 11 Hub genes with notable significance for prognosis of patients were screened. Furtherly, using IHC database of HPA, we confirmed the above candidate Hub genes, and 10 Hub genes that associated with prognosis of GC were identified, namely BGN, CEP55, COL1A2, COL4A1, FZD2, MAOA, PDGFRB, SPARC, TIMP1 and VCAN. CONCLUSION The 10 Hub genes may be the potential biomarkers for predicting the prognosis of GC, which can provide new strategies and methods for the diagnosis and treatment of GC.
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Affiliation(s)
- Long-Kuan Yin
- Department of Gastrointestinal Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
- Sichuan Key Laboratory of Medical Imaging, North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| | - Hua-Yan Yuan
- Department of Gastrointestinal Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| | - Jian-Jun Liu
- Department of Gastrointestinal Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| | - Xiu-Lian Xu
- Department of Gastrointestinal Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| | - Wei Wang
- Department of Gastrointestinal Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| | - Xiang-Yu Bai
- Department of Gastrointestinal Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
- Sichuan Key Laboratory of Medical Imaging, North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| | - Pan Wang
- Department of Gastrointestinal Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
- Sichuan Key Laboratory of Medical Imaging, North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
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12
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Skubleny D, Lin A, Garg S, McLean R, McCall M, Ghosh S, Spratlin JL, Schiller D, Rayat G. Increased CD4/CD8 Lymphocyte ratio predicts favourable neoadjuvant treatment response in gastric cancer: A prospective pilot study. World J Gastrointest Oncol 2023; 15:303-317. [PMID: 36908322 PMCID: PMC9994053 DOI: 10.4251/wjgo.v15.i2.303] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 11/25/2022] [Accepted: 01/12/2023] [Indexed: 02/14/2023] Open
Abstract
BACKGROUND Despite optimal neoadjuvant chemotherapy only 40% of gastric cancer tumours achieve complete or partial treatment response. In the absence of treatment response, neoadjuvant chemotherapy in gastric cancer contributes to adverse events without additional survival benefit compared to adjuvant treatment or surgery alone. Additional strategies and methods are required to optimize the allocation of existing treatment regimens such as FLOT chemotherapy (5-Fluorouracil, Leucovorin, Oxaliplatin and Docetaxel). Predictive biomarkers detected using immunohistochemistry (IHC) methods may provide useful data regarding treatment response.
AIM To investigate the utility of CD4, CD8, Galectin-3 and E-cadherin in predicting neoadjuvant FLOT chemotherapy tumour response in gastric adenocarcinoma.
METHODS Forty-three adult patients with gastric adenocarcinoma, of which 18 underwent neoadjuvant chemotherapy, were included in a prospective clinical cohort. Endoscopic biopsies were obtained from gastric cancer and normal adjacent gastric mucosa. Differences in expression of Galectin-3, E-cadherin, CD4+ and CD8+ molecules between tumours with and without treatment response to neoadjuvant chemotherapy were assessed with IHC. Treatment response was graded by clinical pathologists using the Tumour Regression Score according to the College of American Pathologists criteria. Treatment response was defined as complete or near complete tumour response, whereas partial or poor/no response was defined as incomplete. Digital IHC images were annotated and quantitatively assessed using QuPath 0.3.1. Biomarker expression between responsive and incomplete response tumours was assessed using a two-sided Wilcoxon test. Biomarker expression was also compared between normal and cancer tissue and between 15 paired tumour samples before and after chemotherapy. We performed a preliminary multivariate analysis and power analysis to guide future study. Statistical analyses were completed using R 4.1.2.
RESULTS The ratio between CD4+ and CD8+ lymphocytes was significantly greater in treatment responsive tumours (Wilcoxon, P = 0.03). In univariate models, CD4+/CD8+ ratio was the only biomarker that significantly predicted favourable treatment response (Accuracy 86%, P < 0.001). Using a glmnet multivariate model, high CD4+/CD8+ ratio and low Galectin-3 expression were the most influential variables in predicting a favourable treatment response. Analyses of paired samples found that FLOT chemotherapy also results in increased expression of CD4+ and CD8+ tumour infiltrating lymphocytes (Paired Wilcoxon, P = 0.002 and P = 0.008, respectively). Our power analysis suggests future study requires at least 35 patients in each treatment response group for CD8 and Galectin-3 molecules, whereas 80 patients in each treatment response group are required to assess CD4 and E-cadherin biomarkers.
CONCLUSION We demonstrate that an elevated CD4+/CD8+ Ratio is a promising IHC-based biomarker to predict favourable treatment response to FLOT neoadjuvant chemotherapy in locally advanced gastric cancer.
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Affiliation(s)
- Daniel Skubleny
- Department of Surgery, University of Alberta, Edmonton T6G 2R3, AB, Canada
| | - Andrea Lin
- Department of Surgery, University of Alberta, Edmonton T6G 2R3, Alberta, Canada
| | - Saurabh Garg
- Department of Surgery, University of Alberta, Edmonton T6G 2R3, Alberta, Canada
| | - Ross McLean
- Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton T6G 2R3, Alberta, Canada
| | - Michael McCall
- Department of Surgery, University of Alberta, Edmonton T6G 2R3, Alberta, Canada
| | - Sunita Ghosh
- Department of Oncology, University of Alberta, Edmonton T6G 2R3, Alberta, Canada
| | - Jennifer L Spratlin
- Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton T5G 1Z2, AB, Canada
| | - Daniel Schiller
- Department of Surgery, University of Alberta, Edmonton T6G 2R3, Alberta, Canada
| | - Gina Rayat
- Department of Surgery, University of Alberta, Edmonton T6G 2R3, Alberta, Canada
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13
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Li HX, Wang SQ, Lian ZX, Deng SL, Yu K. Relationship between Tumor Infiltrating Immune Cells and Tumor Metastasis and Its Prognostic Value in Cancer. Cells 2022; 12:cells12010064. [PMID: 36611857 PMCID: PMC9818185 DOI: 10.3390/cells12010064] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 12/16/2022] [Accepted: 12/20/2022] [Indexed: 12/28/2022] Open
Abstract
Tumor metastasis is an important reason for the difficulty of tumor treatment. Besides the tumor cells themselves, the tumor microenvironment plays an important role in the process of tumor metastasis. Tumor infiltrating immune cells (TIICs) are one of the main components of TME and plays an important role in every link of tumor metastasis. This article mainly reviews the role of tumor-infiltrating immune cells in epithelial mesenchymal transformation, extracellular matrix remodeling, tumor angiogenesis and formation of pre-metastatic niche. The value of TIICs in the prognosis of cervical cancer, lung cancer and breast cancer was also discussed. We believe that accurate prognosis of cancer treatment outcomes is conducive to further improving treatment regimens, determining personalized treatment strategies, and ultimately achieving successful cancer treatment. This paper elucidates the relationship between tumor and TIICs in order to explore the function of immune cells in different diseases and provide new ideas for the treatment of cancer.
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Affiliation(s)
- Huan-Xiang Li
- College of Animal Science and Technology, China Agricultural University, Beijing 100193, China
| | - Shu-Qi Wang
- College of Animal Science and Technology, China Agricultural University, Beijing 100193, China
| | - Zheng-Xing Lian
- College of Animal Science and Technology, China Agricultural University, Beijing 100193, China
| | - Shou-Long Deng
- National Health Commission (NHC) of China Key Laboratory of Human Disease Comparative Medicine, Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing 100021, China
- Correspondence: (S.-L.D.); (K.Y.)
| | - Kun Yu
- College of Animal Science and Technology, China Agricultural University, Beijing 100193, China
- Correspondence: (S.-L.D.); (K.Y.)
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14
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Li H, Lin D, Yu Z, Li H, Zhao S, Hainisayimu T, Liu L, Wang K. A nomogram model based on the number of examined lymph nodes-related signature to predict prognosis and guide clinical therapy in gastric cancer. Front Immunol 2022; 13:947802. [PMID: 36405735 PMCID: PMC9667298 DOI: 10.3389/fimmu.2022.947802] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 09/30/2022] [Indexed: 01/25/2023] Open
Abstract
BACKGROUND Increasing evidence suggests that the number of examined lymph nodes (ELNs) is strongly linked to the survivorship of gastric cancer (GC). The goal of this study was to assess the prognostic implications of the ELNs number and to construct an ELNs-based risk signature and nomogram model to predict overall survival (OS) characteristics in GC patients. METHODS This inception cohort study included 19,317 GC patients from the U.S. Surveillance, Epidemiology, and End Results (SEER) database, who were separated into a training group and an internal validation group. The nomogram was built with the training set, then internally verified with SEER data, and externally validated with two different data sets. Based on the RNA-seq data, ELNs-related DERNAs (DElncRNAs, DEmiRNAs, andDEmRNAs) and immune cells were identified. The LASSO-Cox regression analysis was utilized to construct ELNs-related DERNAs and immune cell prognostic signature in The Cancer Genome Atlas (TCGA) cohort. The OS of subgroups with high- and low-ELN signature was compared using the Kaplan-Meier (K-M) analysis. A nomogram was successfully constructed based on the ELNs signature and other clinical characteristics. The concordance index (C-index), calibration plot, receiver operating characteristic curve, and decision curve analysis (DCA) were all used to evaluate the nomogram model. The meta-analysis, the Gene Expression Profiling Interactive Analysis database, and reverse transcription-quantitative PCR (RT-qPCR) were utilized to validate the RNA expression or abundance of prognostic genes and immune cells between GC tissues and normal gastric tissues, respectively. Finally, we analyzed the correlations between immune checkpoints, chemotherapy drug sensitivity, and risk score. RESULTS The multivariate analysis revealed that the high ELNs improved OS compared with low ELNs (hazard ratio [HR] = 0.659, 95% confidence interval [CI]: 0.626-0.694, p < 0.0001). Using the training set, a nomogram incorporating ELNs was built and proven to have good calibration and discrimination (C-index [95% CI], 0.714 [0.710-0.718]), which was validated in the internal validation set (C-index [95% CI], 0.720 [0.714-0.726]), the TCGA set (C-index [95% CI], 0.693 [0.662-0.724]), and the Chinese set (C-index [95% CI], 0.750 [0.720-0.782]). An ELNs-related signature model based on ELNs group, regulatory T cells (Tregs), neutrophils, CDKN2B-AS1, H19, HOTTIP, LINC00643, MIR663AHG, TMEM236, ZNF705A, and hsa-miR-135a-5p was constructed by the LASSO-Cox regression analysis. The result showed that OS was remarkably lower in patients with high-ELNs signature compared with those with low-ELN signature (HR = 2.418, 95% CI: 1.804-3.241, p < 0.001). This signature performed well in predicting 1-, 3-, and 5-year survival (AUC [95% CI] = 0.688 [0.612-0.763], 0.744 [0.659-0.830], and 0.778 [0.647-0.909], respectively). The multivariate Cox analysis illustrated that the risk score was an independent predictor of survival for patients with GC. Moreover, the expression of prognostic genes (LINC00643, TMEM236, and hsa-miR-135a-5p) displayed differences between GC tissues and adjacent non-tumor tissues. The C-index of the nomogram that can be used to predict the OS of GC patients was 0.710 (95% CI: 0.663-0.753). Both the calibration plots and DCA showed that the nomogram has good predictive performance. Moreover, the signature was significantly correlated with the N stage and T stage. According to our analysis, GC patients in the low-ELN signature group may have a better immunotherapy response and OS outcome. CONCLUSIONS We explored the prognostic role of ELNs in GC and successfully constructed an ELNs signature linked to the GC prognosis in TCGA. The findings manifested that the signature is a powerful predictive indicator for patients with GC. The signature might contain potential biomarkers for treatment response prediction for GC patients. Additionally, we identified a novel and robust nomogram combining the characteristics of ELNs and clinical factors for predicting 1-, 3-, and 5-year OS in GC patients, which will facilitate personalized survival prediction and aid clinical decision-making in GC patients.
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Affiliation(s)
- Huling Li
- School of Public Health, Xinjiang Medical University, Urumqi, China
| | - Dandan Lin
- School of Public Health, Xinjiang Medical University, Urumqi, China
| | - Zhen Yu
- Department of Gastrointestinal Surgery, The Third Affiliated Hospital, Xinjiang Medical University, Urumqi, China
| | - Hui Li
- Central Laboratory of Xinjiang Medical University, Urumqi, China
| | - Shi Zhao
- JC School of Public Health and Primary Care, Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Tuersun Hainisayimu
- Department of Biochemistry and Molecular Biology, Basic Medicine School, Xinjiang Medical University, Urumqi, China
| | - Lin Liu
- Department of Gastrointestinal Surgery, The Third Affiliated Hospital, Xinjiang Medical University, Urumqi, China,*Correspondence: Kai Wang, ; Lin Liu,
| | - Kai Wang
- Department of Medical Engineering and Technology, Xinjiang Medical University, Urumqi, China,*Correspondence: Kai Wang, ; Lin Liu,
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15
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Zawati I, Adouni O, Manai M, Nagara M, Tacam M, Reduzzi C, Gamoudi A, Manai M. FOXP3+/CD68+ ratio within the tumor microenvironment may serve as a potential prognostic factor in classical Hodgkin lymphoma. Hum Immunol 2022; 83:843-856. [PMID: 36068099 DOI: 10.1016/j.humimm.2022.08.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Revised: 08/21/2022] [Accepted: 08/23/2022] [Indexed: 11/19/2022]
Abstract
Classical Hodgkin lymphoma (CHL) is characterized by extensive inflammatory immune cells, which predict the disease prognosis. Therefore, this study aimed to explore the significance of different tumor-infiltrated immune cells and subpopulation ratios observed in the tumor microenvironment of CHL, particularly relating to the disease's prognosis-focusing on overall survival (OS) and event-free survival (EFS). Utilizing immunohistochemistry, the quantification and exploration of selected immune cells' subsets, including CD3+, CD4+, CD8+, FOXP3+, CD20+, and CD68+ were conducted on 102 histological samples with primary CHL. Eosinophils were pathologically assessed. Besides, we determined the ratios between different tumor-infiltrated immune cells for each patient. Kaplan-Meier method and Cox regression modeling were used for survival analysis. We demonstrated that among all ratios and immune cells individually, only a higher FOXP3+/CD68+ ratio (≥1.36 cutoff) displayed a tendency towards a favorable OS (p = 0.057, HR = 0.43 [0.18-1.02]) and EFS (p = 0.067, HR = 0.44 [0.18-1.06]) using Cox regression modeling. Moreover, the Kaplan-Meier method showed an association of a higher FOXP3+/CD68+ ratio with a longer 5-years OS (p = 0.037) and a tendency to a better EFS (p = 0.051); however, neither the combined FOXP3+ and CD68+ nor FOXP3+ or CD68+ separately was correlated to the CHL survival. Together, these results demonstrated that the FOXP3+/CD68+ ratio could predict the outcomes of CHL, providing more informative significance than FOXP3+ and CD68+ combined or FOXP3+ and CD68+ individually and might be a potential indicator of risk stratification, which has an important value for guiding the clinical treatment.
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Affiliation(s)
- Imen Zawati
- Department of Immuno-Histo-Cytology, Salah Azaiez Institute, 1006 Tunis, Tunisia; Department of Biology, Mycology, Pathologies, and Biomarkers Laboratory (LR16ES05), Faculty of Sciences of Tunis, University of Tunis El Manar, 2092 Ariana, Tunisia.
| | - Olfa Adouni
- Department of Immuno-Histo-Cytology, Salah Azaiez Institute, 1006 Tunis, Tunisia; Department of Biology, Mycology, Pathologies, and Biomarkers Laboratory (LR16ES05), Faculty of Sciences of Tunis, University of Tunis El Manar, 2092 Ariana, Tunisia
| | - Maroua Manai
- Department of Immuno-Histo-Cytology, Salah Azaiez Institute, 1006 Tunis, Tunisia; Laboratory of Human Genetics (LR99ES10), Faculty of Medicine of Tunis, University of Tunis El Manar, 2092 Tunis, Tunisia; Department of Medicine, Division of Hematology-Oncology, Weill Cornell Medicine, 1300 York Ave, 10021 NY, NY, USA
| | - Majdi Nagara
- Inserm, UMR-S 1251, MMG, Faculty of Medicine Timone, Aix Marseille University, Marseille, France
| | - Moisis Tacam
- Department of OB/Gyn, Baylor College of Medicine, Texas Children's Hospital, Houston, TX, USA
| | - Carolina Reduzzi
- Department of Medicine, Division of Hematology-Oncology, Weill Cornell Medicine, 1300 York Ave, 10021 NY, NY, USA
| | - Amor Gamoudi
- Department of Immuno-Histo-Cytology, Salah Azaiez Institute, 1006 Tunis, Tunisia
| | - Mohamed Manai
- Department of Biology, Mycology, Pathologies, and Biomarkers Laboratory (LR16ES05), Faculty of Sciences of Tunis, University of Tunis El Manar, 2092 Ariana, Tunisia
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16
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Song J, Lin Z, Liu Q, Huang S, Han L, Fang Y, Zhong P, Dou R, Xiang Z, Zheng J, Zhang X, Wang S, Xiong B. MiR-192-5p/RB1/NF-κBp65 signaling axis promotes IL-10 secretion during gastric cancer EMT to induce Treg cell differentiation in the tumour microenvironment. Clin Transl Med 2022; 12:e992. [PMID: 35969010 PMCID: PMC9377151 DOI: 10.1002/ctm2.992] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Revised: 07/04/2022] [Accepted: 07/08/2022] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Regulatory T (Treg) cells are important components of the tumour microenvironment (TME) that play roles in gastric cancer (GC) metastasis. Although tumour cells that undergo epithelial-mesenchymal transition (EMT) regulate Treg cell function, their regulatory mechanism in GC remains unclear. METHODS The miR-192-5p was identified by examining three Gene Expression Omnibus GC miRNA expression datasets. RNA immunoprecipitation (RIP) and dual-luciferase reporter assays were conducted to identify interactions between miR-192-5p and RB1. The role of miR-192-5p/RB1 in GC progression was evaluated based on EdU incorporation, wound healing and Transwell assays. An in vitro co-culture assay was performed to measure the effect of miR-192-5p/RB1 on Treg cell differentiation. In vivo experiments were conducted to explore the role of miR-192-5p in GC progression and Treg cell differentiation. RESULTS MiR-192-5p was overexpressed in tumour and was associated with poor prognosis in GC. MiR-192-5p bound to the RB1 3'-untranslated region, resulting in GC EMT, proliferation, migration and invasion. MiR-192-5p/RB1 mediated interleukin-10 (IL-10) secretion by regulating nuclear factor-kappaBp65 (NF-κBp65), affecting Treg cell differentiation. NF-κBp65, in turn, promoted miR-192-5p expression and formed a positive feedback loop. Furthermore, in vivo experiments confirmed that miR-192-5p/RB1 promotes GC growth and Treg cell differentiation. CONCLUSION Collectively, our studies indicate that miR-192-5p/RB1 promotes EMT of tumour cells, and the miR-192-5p/RB1/NF-κBp65 signaling axis induces Treg cell differentiation by regulating IL-10 secretion in GC. Our results suggest that targeting miR-192-5p/RB1/NF-κBp65 /IL-10 may pave the way for the development of new immune treatments for GC.
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Affiliation(s)
- Jialin Song
- Department of Gastrointestinal SurgeryZhongnan Hospital of Wuhan UniversityWuhanChina
- Hubei Key Laboratory of Tumour Biological BehavioursWuhanChina
- Hubei Cancer Clinical Study CenterWuhanChina
| | - Zaihuan Lin
- Department of Gastrointestinal SurgeryZhongnan Hospital of Wuhan UniversityWuhanChina
- Hubei Key Laboratory of Tumour Biological BehavioursWuhanChina
- Hubei Cancer Clinical Study CenterWuhanChina
| | - Qing Liu
- Department of Respiratory and Critical Care MedicineZhongnan Hospital of Wuhan UniversityWuhanChina
- Wuhan Research Center for Infectious Diseases and CancerChinese Academy of Medical SciencesWuhanChina
| | - Sihao Huang
- Department of Gastrointestinal SurgeryZhongnan Hospital of Wuhan UniversityWuhanChina
- Hubei Key Laboratory of Tumour Biological BehavioursWuhanChina
- Hubei Cancer Clinical Study CenterWuhanChina
| | - Lei Han
- Department of Gastrointestinal SurgeryZhongnan Hospital of Wuhan UniversityWuhanChina
- Hubei Key Laboratory of Tumour Biological BehavioursWuhanChina
- Hubei Cancer Clinical Study CenterWuhanChina
| | - Yan Fang
- Department of obstetrics and gynecologyGuangzhou Women and Children's Medical CenterGuangzhouChina
| | - Panyi Zhong
- Department of Gastrointestinal SurgeryZhongnan Hospital of Wuhan UniversityWuhanChina
- Hubei Key Laboratory of Tumour Biological BehavioursWuhanChina
- Hubei Cancer Clinical Study CenterWuhanChina
| | - Rongzhang Dou
- Department of Gastrointestinal SurgeryZhongnan Hospital of Wuhan UniversityWuhanChina
- Hubei Key Laboratory of Tumour Biological BehavioursWuhanChina
- Hubei Cancer Clinical Study CenterWuhanChina
| | - Zhenxian Xiang
- Department of Gastrointestinal SurgeryZhongnan Hospital of Wuhan UniversityWuhanChina
- Hubei Key Laboratory of Tumour Biological BehavioursWuhanChina
- Hubei Cancer Clinical Study CenterWuhanChina
| | - Jinsen Zheng
- Department of Gastrointestinal SurgeryZhongnan Hospital of Wuhan UniversityWuhanChina
- Hubei Key Laboratory of Tumour Biological BehavioursWuhanChina
- Hubei Cancer Clinical Study CenterWuhanChina
| | - Xinyao Zhang
- Department of Gastrointestinal SurgeryZhongnan Hospital of Wuhan UniversityWuhanChina
- Hubei Key Laboratory of Tumour Biological BehavioursWuhanChina
- Hubei Cancer Clinical Study CenterWuhanChina
| | - Shuyi Wang
- Department of Gastrointestinal SurgeryZhongnan Hospital of Wuhan UniversityWuhanChina
- Hubei Key Laboratory of Tumour Biological BehavioursWuhanChina
- Hubei Cancer Clinical Study CenterWuhanChina
| | - Bin Xiong
- Department of Gastrointestinal SurgeryZhongnan Hospital of Wuhan UniversityWuhanChina
- Hubei Key Laboratory of Tumour Biological BehavioursWuhanChina
- Hubei Cancer Clinical Study CenterWuhanChina
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17
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Huang F, Dai C, Zhang Y, Zhao Y, Wang Y, Ru G. Development of Molecular Mechanisms and Their Application on Oncolytic Newcastle Disease Virus in Cancer Therapy. Front Mol Biosci 2022; 9:889403. [PMID: 35860357 PMCID: PMC9289221 DOI: 10.3389/fmolb.2022.889403] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Accepted: 05/10/2022] [Indexed: 11/13/2022] Open
Abstract
Cancer is caused by the destruction or mutation of cellular genetic materials induced by environmental or genetic factors. It is defined by uncontrolled cell proliferation and abnormality of the apoptotic pathways. The majority of human malignancies are characterized by distant metastasis and dissemination. Currently, the most common means of cancer treatment include surgery, radiotherapy, and chemotherapy, which usually damage healthy cells and cause toxicity in patients. Targeted therapy is an effective tumor treatment method with few side effects. At present, some targeted therapeutic drugs have achieved encouraging results in clinical studies, but finding an effective solution to improve the targeting and delivery efficiency of these drugs remains a challenge. In recent years, oncolytic viruses (OVs) have been used to direct the tumor-targeted therapy or immunotherapy. Newcastle disease virus (NDV) is a solid oncolytic agent capable of directly killing tumor cells and increasing tumor antigen exposure. Simultaneously, NDV can trigger the proliferation of tumor-specific immune cells and thus improve the therapeutic efficacy of NDV in cancer. Based on NDV’s inherent oncolytic activity and the stimulation of antitumor immune responses, the combination of NDV and other tumor therapy approaches can improve the antitumor efficacy while reducing drug toxicity, indicating a broad application potential. We discussed the biological properties of NDV, the antitumor molecular mechanisms of oncolytic NDV, and its application in the field of tumor therapy in this review. Furthermore, we presented new insights into the challenges that NDV will confront and suggestions for increasing NDV’s therapeutic efficacy in cancer.
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Affiliation(s)
- Fang Huang
- Cancer Center, Department of Pathology, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, China
| | - Chuanjing Dai
- Cancer Center, Department of Pathology, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, China
- College of Life Sciences and Medicine, Xinyuan Institute of Medicine and Biotechnology, Zhejiang Sci-Tech University, Hangzhou, China
| | - Youni Zhang
- College of Life Sciences and Medicine, Xinyuan Institute of Medicine and Biotechnology, Zhejiang Sci-Tech University, Hangzhou, China
- Department of Laboratory Medicine, Tiantai People’s Hospital, Taizhou, China
| | - Yuqi Zhao
- College of Life Sciences and Medicine, Xinyuan Institute of Medicine and Biotechnology, Zhejiang Sci-Tech University, Hangzhou, China
| | - Yigang Wang
- College of Life Sciences and Medicine, Xinyuan Institute of Medicine and Biotechnology, Zhejiang Sci-Tech University, Hangzhou, China
- *Correspondence: Yigang Wang, ; Guoqing Ru,
| | - Guoqing Ru
- Cancer Center, Department of Pathology, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, China
- *Correspondence: Yigang Wang, ; Guoqing Ru,
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18
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Wang J, Qiu Q, Lian N, Wang H, Zheng Q, Yang Y, Ma Y, Zhao Y, Li P, Lin J, Lu J, Chen Q, Cao L, Lin M, Huang C, Xie J. An immunosuppressive scoring system to predict recurrence and assist in decision regarding postoperative adjuvant treatment in gastric cancer. Am J Cancer Res 2022; 12:2050-2067. [PMID: 35693074 PMCID: PMC9185630] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Accepted: 04/11/2022] [Indexed: 06/15/2023] Open
Abstract
Inhibition of the immune microenvironment is the main cause of tumor recurrence after surgery in patients with gastric cancer (GC). In this study, immunohistochemistry and multiple immunofluorescence staining were used to evaluate immunosuppressive indicators and immune biomarkers in 825 patients with gastric cancer from three centers. We constructed an immunosuppressive recurrence score (IRS) using LASSO Cox regression based on the expression of six immunosuppressive indicators and found that the IRS and IRS-based nomogram were significantly accurate and reliable in predicting recurrence. Moreover, an elevated IRS was associated with locoregional recurrence and postoperative adjuvant chemotherapy failure. Furthermore, an increase in IRS indicated inhibition of the antitumor effect of CD8+ tumor-infiltrating lymphocytes in the invasive margin. Thus, we propose that the IRS can predict the recurrence outcome of patients with GC by distinguishing the immunosuppressive status, which is helpful in the selection of individualized adjuvant treatment plans.
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Affiliation(s)
- Jiabin Wang
- Department of Gastric Surgery, Fujian Medical University Union HospitalFuzhou, Fujian, China
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of EducationFuzhou, Fujian, China
- Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical UniversityFuzhou, Fujian, China
| | - Qingzhu Qiu
- Department of Gastric Surgery, Fujian Medical University Union HospitalFuzhou, Fujian, China
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of EducationFuzhou, Fujian, China
- Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical UniversityFuzhou, Fujian, China
| | - Ningzi Lian
- Department of Gastric Surgery, Fujian Medical University Union HospitalFuzhou, Fujian, China
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of EducationFuzhou, Fujian, China
- Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical UniversityFuzhou, Fujian, China
| | - Huagen Wang
- Department of Gastric Surgery, Fujian Medical University Union HospitalFuzhou, Fujian, China
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of EducationFuzhou, Fujian, China
- Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical UniversityFuzhou, Fujian, China
| | - Qiaoling Zheng
- Department of Pathology, Fujian Medical University Union HospitalFuzhou, Fujian, China
| | - Yinghong Yang
- Department of Pathology, Fujian Medical University Union HospitalFuzhou, Fujian, China
| | - Yubin Ma
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Qinghai UniversityXining, Qinghai, China
| | - Yajun Zhao
- Department of Gastrointestinal Surgery, West District of The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of ChinaHefei, Anhui, China
| | - Ping Li
- Department of Gastric Surgery, Fujian Medical University Union HospitalFuzhou, Fujian, China
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of EducationFuzhou, Fujian, China
- Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical UniversityFuzhou, Fujian, China
| | - Jianxian Lin
- Department of Gastric Surgery, Fujian Medical University Union HospitalFuzhou, Fujian, China
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of EducationFuzhou, Fujian, China
- Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical UniversityFuzhou, Fujian, China
| | - Jun Lu
- Department of Gastric Surgery, Fujian Medical University Union HospitalFuzhou, Fujian, China
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of EducationFuzhou, Fujian, China
- Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical UniversityFuzhou, Fujian, China
| | - Qiyue Chen
- Department of Gastric Surgery, Fujian Medical University Union HospitalFuzhou, Fujian, China
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of EducationFuzhou, Fujian, China
- Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical UniversityFuzhou, Fujian, China
| | - Longlong Cao
- Department of Gastric Surgery, Fujian Medical University Union HospitalFuzhou, Fujian, China
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of EducationFuzhou, Fujian, China
- Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical UniversityFuzhou, Fujian, China
| | - Mi Lin
- Department of Gastric Surgery, Fujian Medical University Union HospitalFuzhou, Fujian, China
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of EducationFuzhou, Fujian, China
- Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical UniversityFuzhou, Fujian, China
| | - Changming Huang
- Department of Gastric Surgery, Fujian Medical University Union HospitalFuzhou, Fujian, China
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of EducationFuzhou, Fujian, China
- Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical UniversityFuzhou, Fujian, China
| | - Jianwei Xie
- Department of Gastric Surgery, Fujian Medical University Union HospitalFuzhou, Fujian, China
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of EducationFuzhou, Fujian, China
- Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical UniversityFuzhou, Fujian, China
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Kim EY, Abdul-Ghafar J, Chong Y, Yim K. Calculated Tumor-Associated Neutrophils Are Associated with the Tumor−Stroma Ratio and Predict a Poor Prognosis in Advanced Gastric Cancer. Biomedicines 2022; 10:biomedicines10030708. [PMID: 35327509 PMCID: PMC8945075 DOI: 10.3390/biomedicines10030708] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 03/17/2022] [Accepted: 03/17/2022] [Indexed: 11/23/2022] Open
Abstract
The tumor-associated neutrophils (TANs) value and tumor—stroma ratio (TSR) are promising prognostic parameters in the tumor microenvironment. We aimed to evaluate the prognostic role and relationship of TANs and TSR in gastric cancer. Our study comprised 157 patients who underwent gastrectomy for advanced gastric cancer. TANs were assessed by immunohistochemical staining (CD15 and CD66b) and were analyzed with an image analyzer. TANs have been known to have different functional subpopulations of N1 (anti-tumor) and N2 (pro-tumor). We developed “calculated TANs with pro-tumor function (cN2; CD15 minus CD66b)”. The TSR was evaluated using hematoxylin and eosin staining. High-grade CD15-positive, cN2 in the tumor center, and TSR were significantly related to poor disease-free survival (DFS). TSR and cN2 were independent prognostic factors for DFS (hazard ratio (HR) = 2.614; p = 0.001, HR = 3.976; p = 0.002) and cN2 in the tumor center showed a positive correlation with TSR (R = 0.179, p = 0.025). While CD66b stained both N1 and N2, CD15 detected most of N2. Combining both markers revealed a novel cN2, which was an independent marker of poor prognosis. The transformation from N1 to N2 predominantly occurred in the tumor center, and was associated with TSR.
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Affiliation(s)
- Eun Young Kim
- Department of Surgery, Uijeongbu St. Mary Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea;
| | - Jamshid Abdul-Ghafar
- Department of Hospital Pathology, Uijeongbu St. Mary Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea; (J.A.-G.); (Y.C.)
| | - Yosep Chong
- Department of Hospital Pathology, Uijeongbu St. Mary Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea; (J.A.-G.); (Y.C.)
| | - Kwangil Yim
- Department of Hospital Pathology, Uijeongbu St. Mary Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea; (J.A.-G.); (Y.C.)
- Correspondence: ; Tel.: +82-31-820-5346
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20
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Ren Y, Chen Z, Sun J, Cai Y, Chen Z, Chen X, Wu W. The correlation between infiltration of FoxP3 + Tregs, CD66b + TANs and CD163 + TAMs in colorectal cancer. Cent Eur J Immunol 2022; 47:1-7. [PMID: 35600158 PMCID: PMC9115591 DOI: 10.5114/ceji.2022.114004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Accepted: 02/08/2022] [Indexed: 11/17/2022] Open
Abstract
Introduction The infiltration of immune cells in tumor tissue is affected by the tumor microenvironment. However, the relationship between the infiltration of regulatory T cells (Tregs), tumor-associated neutrophils (TANs) and tumor-associated macrophages (TAMs) in colorectal cancer (CRC) remains unclear. Material and methods Tissue microarray and immunohistochemistry were used to detect the infiltration of FoxP3+ Tregs, CD66b+ TANs and CD163+ TAMs in 249 CRC samples (training cohort) and 243 CRC samples (validation cohort). The relationship between two cells was evaluated by Spearman's rank correlation coefficient and comparison between two groups was analyzed by Mann-Whitney U test. Results The continuous variable positive cell numbers were non-normally distributed. Spearman correlation analysis showed that CD66b+ TAN level in cancer tissues was negatively related to FoxP3+ Treg level (correlation coefficient: -0.495, p < 0.05) and CD163+ TAM level (correlation coefficient: -0.266, p < 0.05), and FoxP3+ Treg level was positively related to CD163+ TAM level (correlation coefficient: 0.467, p < 0.05) in the training cohort. The numbers of FoxP3+ Tregs were significantly different between low and high CD66b+ TAN level groups (p < 0.001), as well as that of CD66b+ TANs in low and high CD163+ TAM level groups and CD163+ TAMs in different FoxP3+ Treg level groups. The results of the validation cohort were similar to those of the training cohort. Conclusions There is a negative correlation between infiltration of CD66b+ TANs and that of FoxP3+ Tregs or CD163+ TAMs, and a positive correlation between infiltration of FoxP3+ Tregs and CD163+ TAMs in CRC tissues.
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Affiliation(s)
- Yuehan Ren
- Department of Colorectal and Anal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China
| | - Zhiyuan Chen
- Department of Microbiology and Immunology, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang Province, China
| | - Jiancheng Sun
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China
| | - Yiqi Cai
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China
| | - Zhejing Chen
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China
| | - Xiaolei Chen
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China
| | - Wenyi Wu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China
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21
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Immune Score Predicts Outcomes of Gastric Cancer Patients Treated with Adjuvant Chemoradiotherapy. JOURNAL OF ONCOLOGY 2022; 2021:9344124. [PMID: 34987582 PMCID: PMC8723845 DOI: 10.1155/2021/9344124] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Accepted: 11/01/2021] [Indexed: 02/06/2023]
Abstract
Background Substantial evidence has demonstrated that tumor-infiltrating lymphocytes (TILs) are correlated with patient prognosis. The TIL-based immune score (IS) affects prognosis in various cancers, but its prognostic impact in gastric cancer (GC) patients treated with adjuvant chemoradiotherapy remains unclear. Methods A total of 101 GC patients who received chemoradiotherapy after gastrectomy were retrospectively analyzed in this study. Immunohistochemistry staining for CD3+ and CD8+ T-cell counts in both tumor center (CT) and invasive margin (IM) regions was built into the IS. Patients were then divided into three groups based on their differential IS levels. The correlation between IS and clinical parameters was analyzed. The prognostic impact of IS and clinical parameters was evaluated using Kaplan-Meier analysis and Cox proportional hazard regression analysis. Receiver operating characteristic (ROC) curves were plotted to compare the area under the curve (AUC) of IS with other clinical parameters. Nomograms for disease-free survival (DFS) and overall survival (OS) prediction were constructed based on the identified parameters. Results Finally, 20 (19.8%), 57 (56.4%), and 24 (23.8%) GC patients were identified with low, intermediate, and high IS levels, respectively. GC patients with higher IS levels exhibited better DFS (p < 0.001) and OS (p < 0.001). IS was an independent prognostic factor for both DFS (p < 0.001) and OS (p < 0.001) in multivariate analysis. IS presented a better predictive ability than the traditional pathological tumor-node-metastasis (pTNM) staging system (AUC: 0.801 vs. 0.677 and 0.800 vs. 0.660, respectively) with respect to both DFS and OS. The C-index of the nomograms for DFS and OS prediction was 0.737 and 0.774, respectively. Conclusions IS is a strong predictive factor for both DFS and OS in GC patients treated with adjuvant chemoradiotherapy, which may complement the traditional pTNM staging system.
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22
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Yu H, Li E, Liu S, Wu Z, Gao F. Identification of Signature Genes in the PD-1 Relative Gastric Cancer Using a Combined Analysis of Gene Expression and Methylation Data. JOURNAL OF ONCOLOGY 2022; 2022:4994815. [PMID: 36568638 PMCID: PMC9780002 DOI: 10.1155/2022/4994815] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 08/03/2022] [Accepted: 08/06/2022] [Indexed: 12/23/2022]
Abstract
BACKGROUND The morbidity and mortality rates for gastric cancer (GC) rank second among all cancers, indicating the serious threat it poses to human health, as well as human life. This study aims to identify the pathways and genes as well as investigate the molecular mechanisms of tumor-related genes in gastric cancer (GC). METHOD We compared differentially expressed genes (DEGs) and differentially methylated genes (DMGs) in gastric cancer and normal tissue samples using The Cancer Genome Atlas (TCGA) data. The Kyoto Encyclopedia of Gene and Genome (KEGG) and the Gene Ontology (GO) enrichment analysis' pathway annotations were conducted on DMGs and DEGs using a clusterProfiler R package to identify the important functions, as well as the biological processes and pathways involved. The intersection of the two was chosen and defined as differentially methylated and expressed genes (DMEGs). For DMEGs, we used the principal component analysis (PCA) to differentiate gastric cancer from adjacent samples. The linear discriminant analysis method was applied to categorize the samples using DMEGs methylation data and DMEGs expression profiles data and was validated using the leave-one-out cross-validation (LOOCV) method. We plotted the ROC curve for the classification and calculated the AUC (area under the ROC curve) value for a more intuitive view of the classification effect. We also used the NetworkAnalyst 3.0 tool to analyze DMEGs, using DrugBank to acquire information on protein-drug interactions and generate a network map of gene-drug interactions. RESULTS We identified a total of 971 DMGs in 188 PD-1 negative and 187 PD-1 positive gastric cancer samples obtained from TCGA. The KEGG and GO enrichment analysis showed the involvement of the regulation of ion transmembrane transport, collagen-containing extracellular matrix, cell-cell junction, and peptidase regulator activity. We simultaneously obtained 1,189 DEGs, out of which 986 were downregulated, while 203 were upregulated in tumors. The enriched analysis of the GO's and KEGG's pathways indicated that the most significant pathways included an intestinal immune network for IgA production, Staphylococcus aureus infection, cytokine-cytokine receptor interaction, and viral protein interaction with cytokine and cytokine receptor, which have previously been linked with gastric cancer. The compound DB01830 can bind well to the active site of the LCK protein and shows good stability, thus making it a potential inhibitor of the LCK protein. To observe the relationship between DMEGs' expression and prognosis, we observed 10 genes, among which were TRIM29, TSPAN8, EOMES, PPP1R16B, SELL, PCED1B, IYD, JPH1, CEACAM5, and RP11-44K6.2. Their high expressions were related to high risks. Besides, those genes were validated in different internal and external validation sets. CONCLUSION These results may provide potential molecular biological therapy for PD-1 negative gastric cancer.
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Affiliation(s)
- Han Yu
- Department of Gastrointestinal Surgery, Meizhou People's Hospital, Huangtang Road, Meijiang District, Meizhou 514031, Guangdong Province, China
| | - En Li
- Department of Gastrointestinal Surgery, Meizhou People's Hospital, Huangtang Road, Meijiang District, Meizhou 514031, Guangdong Province, China
| | - Sha Liu
- Department of Gastrointestinal Surgery, Meizhou People's Hospital, Huangtang Road, Meijiang District, Meizhou 514031, Guangdong Province, China
| | - ZuGuang Wu
- Department of Gastrointestinal Surgery, Meizhou People's Hospital, Huangtang Road, Meijiang District, Meizhou 514031, Guangdong Province, China
| | - FenFei Gao
- Department of Pharmacology, Shantou University Medical College, 22 Xinling Road, Shantou 515041, Guangdong Province, China
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Kim H, Heo YJ, Cho YA, Kang SY, Ahn S, Kim KM. Tumor immune microenvironment is influenced by frameshift mutations and tumor mutational burden in gastric cancer. Clin Transl Oncol 2021; 24:556-567. [PMID: 34767183 DOI: 10.1007/s12094-021-02714-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Accepted: 09/23/2021] [Indexed: 02/05/2023]
Abstract
PURPOSE Immunoscore can effectively predict prognosis in patients with colon cancer; however, its clinical application is limited. We modified the Immunoscore and created a tumor immune microenvironment (TIM) classification system for gastric carcinoma. Unlike previous studies that used small sample sizes or focused on particular immune-cell subtypes, our simplified system enables pathologists to classify gastric carcinomas intuitively using H&E-stained sections. METHODS Samples from 326 patients with advanced gastric carcinoma were reviewed and analyzed by pathologists using simple determination and digital image analysis. Comprehensive results of cancer-panel sequencing, Epstein-Barr‒virus (EBV) status, and PD-L1, HER2, ATM, PTEN, MET, FGFR2, and EGFR immunohistochemistry were evaluated with respect to the TIM class. RESULTS The TIM was classified as "hot" (n = 22), "immunosuppressed" (n = 178), "excluded" (n = 83), or "cold" (n = 43). TIM category was significantly associated with numbers of frameshift mutations (P < 0.001) and high tumor mutational burden (P < 0.004), and predicted overall survival. It was also significantly associated with age, histological type, degree of fibrosis, PD-L1 expression, loss of ATM and PTEN expression (P < 0.001), sex, EBV positivity, and HER2 overexpression (P < 0.04). "Hot" tumors were frequent in PD-L1 expressing and EBV-positive samples, and in those with ATM and PTEN loss. "Excluded" tumors were frequent in HER2-positive cases, whereas "cold" tumors were more frequent in younger patients with poorly cohesive histology and high fibrosis levels. CONCLUSIONS TIM classification system for gastric carcinoma has prognostic significance and results in classes that are associated with molecular characteristics.
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Affiliation(s)
- H Kim
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Y J Heo
- The Samsung Advanced Institute for Health Sciences & Technology (SAIHST), Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Y A Cho
- Department of Pathology, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, Republic of Korea
| | - S Y Kang
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - S Ahn
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - K -M Kim
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. .,The Samsung Advanced Institute for Health Sciences & Technology (SAIHST), Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
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24
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Huang S, Ma L, Lan B, Liu N, Nong W, Huang Z. Comprehensive analysis of prognostic genes in gastric cancer. Aging (Albany NY) 2021; 13:23637-23651. [PMID: 34686626 PMCID: PMC8580339 DOI: 10.18632/aging.203638] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Accepted: 10/03/2021] [Indexed: 12/16/2022]
Abstract
Background: Gastric cancer is associated with high mortality, and effective methods for predicting prognosis are lacking. We aimed to identify potential prognostic markers associated with the development of gastric cancer through bioinformatic analyses. Methods: Gastric cancer-associated gene expression profiles were obtained from The Cancer Genome Atlas and Gene Expression Omnibus databases. The key genes involved in the development of gastric cancer were obtained by differential expression analysis, coexpression analysis, and short time-series expression miner (STEM) analysis. The potential prognostic value of differentially expressed genes was further evaluated using a Cox regression model and risk scores. Hierarchical clustering was applied to validate the impact of key genes on the overall survival of gastric cancer patients. Results: A total of 1381 genes were consistently dysregulated in the development of gastric cancer. Among them, 186 genes affected the overall survival of gastric cancer patients. The following genes had areas under the receiver operating characteristic curve greater than 0.9 in both datasets and were therefore considered key genes: ADAM12, CEP55, LRFN4, INHBA, ADH1B, DPT, FAM107A, and LOC100506388. LRFN4, DPT, and LOC100506388 were identified as potential prognostic genes for gastric cancer through a nomogram. Overexpression of LRFN4 and LOC100506388 was associated with a higher risk of gastric cancer. Finally, we found that tumors were infiltrated with high levels of Th2 cells and mast cells, and the infiltration levels were associated with overall survival in gastric cancer patients. Conclusions: We found that key dysregulated genes may have a prognostic value for the development of gastric cancer.
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Affiliation(s)
- Shaohua Huang
- Department of General Surgery, Affiliated Minzu Hospital of Guangxi Medical University, Nanning, China
| | - Liping Ma
- Department of Clinical Laboratory, Affiliated Minzu Hospital of Guangxi Medical University, Nanning, China
| | - Biyang Lan
- Department of General Surgery, Affiliated Minzu Hospital of Guangxi Medical University, Nanning, China
| | - Ning Liu
- Department of General Surgery, Affiliated Minzu Hospital of Guangxi Medical University, Nanning, China
| | - Wenwei Nong
- Department of General Surgery, Affiliated Minzu Hospital of Guangxi Medical University, Nanning, China
| | - Zhihu Huang
- Department of Clinical Laboratory, Affiliated Minzu Hospital of Guangxi Medical University, Nanning, China
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Hu M, Zou L, Lu J, Yang Z, Chen Y, Xu Y, Sun C. Construction of a 5-feature gene model by support vector machine for classifying osteoporosis samples. Bioengineered 2021; 12:6821-6830. [PMID: 34622712 PMCID: PMC8806423 DOI: 10.1080/21655979.2021.1971026] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Osteoporosis is a progressive bone disease in the elderly and lacks an effective classification method of patients. This study constructed a gene signature for an accurate prediction and classification of osteoporosis patients. Three gene expression datasets of osteoporosis samples were acquired from the Gene Expression Omnibus database with pre-set criteria. Differentially expressed genes (DEGs) between normal and diseased osteoporosis samples were screened using Limma package in R language. Protein–protein interaction (PPI) network was established based on interaction data of the DEGs from the Human Protein Reference Database. Classification accuracy of the classifier was assessed with sensitivity, specificity and area under curve (AUC) using the pROC package in the R. Pathway enrichment analysis was performed on feature genes with clusterProfiler. A total of 310 differentially expressed genes between two samples were associated with positive regulation of protein secretion and cytokine secretion, neutrophil-mediated immunity, and neutrophil activation. PPI network of DEGs consisted of 12 genes. A SVM classifier based on five feature genes was developed to classify osteoporosis samples, showing a higher prediction accuracy and AUC for GSE35959, GSE62402, GSE13850, GSE56814, GSE56815 and GSE7429 datasets. A SVM classifier with a high accuracy was developed for predicting osteoporosis. The genes included may be the potential feature genes in osteoporosis development.AbbreviationsDEGs: Differentially expressed genes; PPI: protein–protein interaction; WHO: World Health Organization; SVM: Support vector machine; GEO: Gene Expression Omnibus; KEGG: Kyoto Encyclopedia of Genes and Genomes; GO: Gene Ontology; BP: Biological Process; CC: Cellular Component; MF: Molecular Function; SVM: Support vector machines
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Affiliation(s)
- Minwei Hu
- Department of Orthopedics, Ruijin Hospital LuWan Branch, School of Medicine, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Ling Zou
- Department of Orthopedics, Ruijin Hospital LuWan Branch, School of Medicine, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Jiong Lu
- Department of Orthopedics, Ruijin Hospital LuWan Branch, School of Medicine, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Zeyu Yang
- Department of Orthopedics, Ruijin Hospital LuWan Branch, School of Medicine, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Yinan Chen
- Department of Orthopedics, Ruijin Hospital LuWan Branch, School of Medicine, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Yaozeng Xu
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Changhui Sun
- Department of Orthopedics, Ruijin Hospital LuWan Branch, School of Medicine, Shanghai Jiaotong University School of Medicine, Shanghai, China
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Nema R, Patel P, Kumar A. Prognostic Role of Receptor Tyrosine Kinase-Like Orphan Receptors in Intestinal-Type Gastric Cancer. Asian Pac J Cancer Prev 2021; 22:2125-2134. [PMID: 34319035 PMCID: PMC8607102 DOI: 10.31557/apjcp.2021.22.7.2125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Accepted: 07/01/2021] [Indexed: 12/02/2022] Open
Abstract
BACKGROUND Gastric cancer (GC) is diagnosed at advanced stages and has high mortality rates. Surgical resection and adjuvant chemotherapy are the main therapeutic approaches for GC. Despite curative resection, recurrence and metastasis contribute to a high mortality rate in patients with GC. The receptor-tyrosine-kinase-like orphan receptors 1/2 (ROR1/2) are transmembrane proteins belonging to the receptor tyrosine kinase (RTK) family. ROR1 and ROR2 are known to overexpress in the tumor tissues from several types of cancer patients. However, the role of RORs in the prognosis has not been understood. METHODS This study aimed to determine the association of mRNA expression of ROR1, ROR2, and their signaling components WNT5A, NKX2-1, and FOXF1, with the survival outcome of GC patients. We performed Kaplan-Meir survival analysis on publicly available 'The Cancer Genome Atlas (TCGA)' data sets using 'Kaplan-Meir Plotter.' RESULTS High mRNA expression of ROR1, ROR2, NKX2-1, and FOXF1 was significantly correlated with worse overall survival (OS) of GC patients. Interestingly ROR1 and ROR showed a prognostic role in the intestinal subtype, but not in the diffuse subtype of GC. Furthermore, ROR1 was positively correlated with regulatory T cells and M2-type macrophages and negatively correlated with Th17 and natural killer T cells in the tumor stroma of patients with GC. CONCLUSION We conclude that the expression of ROR1, ROR2, and their associated genes correlate with worst prognosis of GC patients, particularly in the intestinal type.
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Affiliation(s)
| | | | - Ashok Kumar
- Department of Biochemistry, All India Institute of Medical Sciences (AIIMS) Bhopal, Saket Nagar, Bhopal, India.
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Gastric Cancer Mesenchymal Stem Cells Inhibit NK Cell Function through mTOR Signalling to Promote Tumour Growth. Stem Cells Int 2021; 2021:9989790. [PMID: 34306099 PMCID: PMC8263240 DOI: 10.1155/2021/9989790] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 06/04/2021] [Accepted: 06/14/2021] [Indexed: 12/11/2022] Open
Abstract
The dysfunction of natural killer (NK) cells has been increasingly reported in malignancies, especially in solid tumours. Mesenchymal stem cells (MSCs) exhibit pleiotropic functions that include mediating immune cell exhaustion which is implicated in cancer progression. However, the association of MSCs derived from gastric cancer (gastric cancer mesenchymal stem cells: GCMSCs) with the dysfunction of NK cells remains poorly understood. In this study, we demonstrated that GCMSCs effectively contributed to the exhaustion of NK cells through the release of soluble factors. Furthermore, passivation of the antitumour effect in NK cells was closely associated with their dysfunctional state. The GCMSC-conditioned medium prevented the frequency and effector function of infiltrating NK cells in tumour-bearing mouse models, thus promoting tumour growth. Mechanistically, mammalian target of rapamycin (mTOR) signalling, a critical regulator of cellular metabolism that mediates the function of immune cells, was inhibited in NK cells treated with GCMSCs. However, the checkpoint receptor PD-1 was still present at minimal levels with or without GCMSCs. The study results revealed that GCMSCs contributed to dysfunctional NK cells involved at least partially in the inhibition of mTOR signalling, suggesting potential directions for NK cell-based cancer immunotherapy.
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28
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Lin T, Peng W, Mai P, Zhang E, Peng L. Human Gastric Cancer Stem Cell (GCSC) Markers Are Prognostic Factors Correlated With Immune Infiltration of Gastric Cancer. Front Mol Biosci 2021; 8:626966. [PMID: 34113647 PMCID: PMC8185345 DOI: 10.3389/fmolb.2021.626966] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Accepted: 04/08/2021] [Indexed: 12/24/2022] Open
Abstract
The prognosis of patients with gastric cancer (GC) is still unsatisfying. Numerous markers of gastric cancer stem cells (GCSCs) have been identified and were thought to be related to cancer aggressiveness. However, the roles of GCSC markers in GC patients’ prognosis and immune infiltration remain unknown. Expression of GCSC markers was analyzed using Oncomine and Gene Expression Profiling Interactive Analysis (GEPIA). Their associations with clinicopathological parameters were analyzed using UALCAN and LinkedOmics. Alternations and protein expression of GCSC markers were analyzed by cBioPortal and the Human Protein Atlas databases, respectively. The prognostic significance of GCSC markers was evaluated using Kaplan-Meier plotter. Correlations between the expression of GCSC markers and immune infiltration along with biomarkers of tumor-infiltrating immune cells (TIICs) were assessed combined Tumor Immune Estimation Resource and GEPIA. GeneMANIA was used to discover the interactive genes of GCSC markers, and enrichment analysis was performed using Database for Annotation, Visualization, and Integrated Discovery server. We identified six GCSC markers significantly up-expressed in GC, compared with normal stomach tissues. Among them, the overexpression of ICAM1, THY1, and CXCR4 significantly indicated adverse, while EPCAM indicated beneficial clinicopathological features of GC patients. The up-regulation of CXCR4 showed unfavorable prognostic significance, whereas EPCAM and TFRC showed the opposite. The six GCSC markers were all correlated with the infiltration and activation of distinct TIICs. Especially, ICAM1, THY1, and CXCR4 showed strongly positive correlations with tumor-associated macrophages. Besides, chemokine, Toll-like receptor, NF-kappa B, and HIF-1 signaling pathways might be involved in the regulation of GCSC markers on cancer development. This study proposed that GCSC markers might be promising targets of GC treatment to weaken cancer stem-like properties and strengthen anticancer immunity.
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Affiliation(s)
- Tong Lin
- The Fourth Clinical Medical School, Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Wenya Peng
- The Fourth Clinical Medical School, Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Peipei Mai
- The Fourth Clinical Medical School, Guangzhou University of Chinese Medicine, Shenzhen, China
| | - E Zhang
- The Fourth Clinical Medical School, Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Lisheng Peng
- Department of Science and Education, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, China
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A risk signature with inflammatory and immune cells infiltration predicts survival and efficiency of chemotherapy in gastric cancer. Int Immunopharmacol 2021; 96:107589. [PMID: 34162126 DOI: 10.1016/j.intimp.2021.107589] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Revised: 02/17/2021] [Accepted: 03/11/2021] [Indexed: 12/24/2022]
Abstract
OBJECTIVE Tumor immune microenvironment biomarkers might add predictive value for outcomes. This study aimed to construct a risk signature with tumor infiltration immune and inflammatory cells to improve the prediction of survival. METHODS A risk signature model in combination with CD66b + neutrophils, CD3+ T, CD8+ T lymphocytes, and FOXP3 + regulatory T cells was developed in a training cohort of 327 GC patients undergoing surgical resection between 2011 and 2012, and validated in a validation cohort of 285 patients from 2012 to 2013. RESULTS The high CD66b expression predicted the poor disease special survival (DSS) and inversely correlated with the CD8 (P < 0.05) and FOXP3 expression (P < 0.05) in the training cohort. This was comparable to the disease-free survival (DFS) findings observed in the validation cohort. Furthermore, a risk stratification was developed from the integration of CD66b + neutrophils and T immune cells. For DFS and DSS, both demonstrated the worse prognosis in the high-risk group, when compared to the low-risk group in both the training cohort and validation cohort (all P < 0.05). In addition, the high-risk group was associated with post-operative relapses, and this risk signature model increased the predictive accuracy and efficiency for post-operative relapses. Moreover, the high-risk group identified a subgroup of GC patients who tended not to benefit from the adjuvant chemotherapy. CONCLUSIONS The incorporation of neutrophils into T lymphocytes could provide more accurate prognostic information in GC and this risk stratification has potential for identifying the subgroup of GC patients who could benefit from adjuvant chemotherapy.
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Yamaguchi T, Kinoshita J, Saito H, Shimada M, Terai S, Moriyama H, Okamoto K, Makino I, Nakamura K, Tajima H, Ninomiya I, Fushida S. High CD8/CD33 ratio in peritoneal metastatic lesions is associated with favorable prognosis in gastric cancer. Cancer Rep (Hoboken) 2021; 4:e1389. [PMID: 33793095 PMCID: PMC8551992 DOI: 10.1002/cnr2.1389] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 03/02/2021] [Accepted: 03/17/2021] [Indexed: 12/13/2022] Open
Abstract
Background Tumor‐infiltrating lymphocytes (TILs) and other immune cells have been reported as a prognostic factor in several tumors, including gastric cancer, and they play an important role in antitumor effect at the primary site. There were few reports on the immune status in peritoneal metastatic lesions for gastric cancer. Aims The aims of this study were to assess the prognostic significance of TILs (CD4, CD8, CD19, regulatory T cells [Tregs]), and myeloid‐derived suppressor cells (MDSCs) in peritoneal metastatic lesions. Methods We retrospectively investigated 60 patients for gastric cancer with peritoneal metastasis who were treated between 2009 and 2016 in our institute. Immunohistochemistry for CD4, CD8, CD19, FOXP3, and CD33 was performed in the peritoneal metastatic lesions. The absolute numbers of immune cells and ratios were evaluated, and the relationship between immune‐related marker and overall survival (OS) was investigated. Results A high infiltration of CD8+ lymphocytes or high CD8/CD33 ratio was a better prognosis for OS in univariate analysis using all immunologic variables (P = .012, P = .001). In multivariate analysis for clinical and immunologic variables, high CD8/CD33 ratio was identified as an independent prognostic factor for OS (Hazard ratio: 0.291, 95% confidence interval: 0.126‐0.670, P = .004). Conclusion High CD8/CD33 ratio and high infiltration of CD8+ lymphocytes in peritoneal metastatic lesions were favorable prognoses for gastric cancer patients with peritoneal metastasis. It is necessary to modify the immune microenvironment result to increase the level of CD8+ lymphocytes in the peritoneal metastatic lesions.
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Affiliation(s)
- Takahisa Yamaguchi
- Department of Gastroenterological Surgery, Division of Cancer Medicine, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
| | - Jun Kinoshita
- Department of Gastroenterological Surgery, Division of Cancer Medicine, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
| | - Hiroto Saito
- Department of Gastroenterological Surgery, Division of Cancer Medicine, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
| | - Mari Shimada
- Department of Gastroenterological Surgery, Division of Cancer Medicine, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
| | - Siro Terai
- Department of Gastroenterological Surgery, Division of Cancer Medicine, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
| | - Hideki Moriyama
- Department of Gastroenterological Surgery, Division of Cancer Medicine, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
| | - Koichi Okamoto
- Department of Gastroenterological Surgery, Division of Cancer Medicine, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
| | - Isamu Makino
- Department of Gastroenterological Surgery, Division of Cancer Medicine, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
| | - Keishi Nakamura
- Department of Gastroenterological Surgery, Division of Cancer Medicine, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
| | - Hidehiro Tajima
- Department of Gastroenterological Surgery, Division of Cancer Medicine, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
| | - Itasu Ninomiya
- Department of Gastroenterological Surgery, Division of Cancer Medicine, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
| | - Sachio Fushida
- Department of Gastroenterological Surgery, Division of Cancer Medicine, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
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31
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Profiles of immune infiltration and its relevance to survival outcome in meningiomas. Biosci Rep 2021; 40:223848. [PMID: 32378707 PMCID: PMC7225412 DOI: 10.1042/bsr20200538] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Revised: 03/31/2020] [Accepted: 05/05/2020] [Indexed: 12/26/2022] Open
Abstract
Tumor-infiltrating immune cells play a decisive part in prognosis and survival. Until now, previous researches have not made clear about the diversity of cell types involved in the immune response. The objective of this work was to confirm the composition of tumor-infiltrating immune cells and their correlation with prognosis in meningiomas based on a metagene approach (known as CIBERSORT) and online databases. A total of 22 tumor-infiltrating immune cells were detected to determine the relationship between the immune infiltration pattern and survival. The proportion of M2 macrophages was more abundant in 68 samples, reaching more than 36%. Univariate Cox regression analysis displayed that the proportion of dendritic cells was obviously related to prognosis. Hierarchical clustering analysis identified two clusters by the method of within sum of squares errors, which exhibited different infiltrating immune cell composition and survival. To summarize, our results indicated that proportions of tumor-infiltrating immune cells as well as cluster patterns were associated with the prognosis, which offered clinical significance for research of meningiomas.
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32
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Ma M, Chen Y, Chong X, Jiang F, Gao J, Shen L, Zhang C. Integrative analysis of genomic, epigenomic and transcriptomic data identified molecular subtypes of esophageal carcinoma. Aging (Albany NY) 2021; 13:6999-7019. [PMID: 33638948 PMCID: PMC7993659 DOI: 10.18632/aging.202556] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Accepted: 12/29/2020] [Indexed: 12/16/2022]
Abstract
Esophageal cancer (EC) involves many genomic, epigenetic and transcriptomic disorders, which play key roles in the heterogeneous progression of cancer. However, the study of EC with multi-omics has not been conducted. This study identified a high consistency between DNA copy number variations and abnormal methylations in EC by analyzing genomics, epigenetics and transcriptomics data and investigating mutual correlations of DNA copy number variation, methylation and gene expressions, and stratified copy number variation genes (CNV-Gs) and methylation genes (MET-Gs). The methylation, CNVs and expression profiles of CNV-Gs and MET-Gs were analyzed by consistent clustering using iCluster integration, here, we determined three subtypes (iC1, iC2, iC3) with different molecular traits, prognostic characteristics and tumor immune microenvironment features. We also identified 4 prognostic genes (CLDN3, FAM221A, GDF15 and YBX2) differentially expressed in the three subtypes, and could therefore be used as representative biomarkers for the three subtypes of EC. In conclusion, by performing comprehensive analysis on genomic, epigenetic and transcriptomic regulations, the current study provided new insights into the multilayer molecular and pathological traits of EC, and contributed to the precision medication for EC patients.
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Affiliation(s)
- Mingyang Ma
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Yang Chen
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Xiaoyi Chong
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Fangli Jiang
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Jing Gao
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital and Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen 518116, China
| | - Lin Shen
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Cheng Zhang
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing 100142, China
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Song Y, Yang K, Sun T, Tang R. Development and validation of prognostic markers in sarcomas base on a multi-omics analysis. BMC Med Genomics 2021; 14:31. [PMID: 33509178 PMCID: PMC7841904 DOI: 10.1186/s12920-021-00876-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Accepted: 01/13/2021] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND In sarcomas, the DNA copy number and DNA methylation exhibit genomic aberrations. Transcriptome imbalances play a driving role in the heterogeneous progression of sarcomas. However, it is still unclear whether abnormalities of DNA copy numbers are systematically related to epigenetic DNA methylation, thus, a comprehensive analysis of sarcoma occurrence and development from the perspective of epigenetic and genomics is required. METHODS RNASeq, copy number variation (CNV), methylation data, clinical follow-up information were obtained from The Cancer Genome Atlas (TCGA) and GEO database. The association between methylation and CNV was analyzed to further identify methylation-related genes (MET-Gs) and CNV abnormality-related genes (CNV-Gs). Subsequently DNA copy number, methylation, and gene expression data associated with the MET-Gs and CNV-Gs were integrated to determine molecular subtypes and clinical and molecular characteristics of molecular subtypes. Finally, key biomarkers were determined and validated in independent validation sets. RESULTS A total of 5354 CNV-Gs and 4042 MET-Gs were screened and showed a high degree of consistency. Four molecular subtypes (iC1, iC2, iC3, and iC4) with different prognostic significances were identified by multiomics cluster analysis, specifically, iC2 had the worst prognosis and iC4 indicated an immune-enhancing state. Three potential prognostic markers (ENO1, ACVRL1 and APBB1IP) were determined after comparing the molecular characteristics of the four molecular subtypes. The expression of ENO1 gene was significantly correlated with CNV, and was noticeably higher in iC2 subtype with the worst prognosis than any other subtypes. The expressions of ACVRL1 and APBB1IP were negatively correlated with methylation, and were high-expressed in the iC4 subtype with the most favorable prognosis. In addition, the number of silent/nonsilent mutations and neoantigens in iC2 subtype were significantly more than those in iC1/iC3/iC4 subtype, and the same trend was also observed in CNV Gain/Loss. CONCLUSION The current comprehensive analysis of genomic and epigenomic regulation provides new insights into multilayered pathobiology of sarcomas. Four molecular subtypes and three prognostic markers developed in this study improve the current understanding of the molecular mechanisms underlying sarcoma.
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Affiliation(s)
- Yongchun Song
- Department of Oncology Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, 710061, Shaanxi, China
| | - Kui Yang
- Department of General Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Tuanhe Sun
- Department of Oncology Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, 710061, Shaanxi, China
| | - Ruixiang Tang
- Department of Oncology Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, 710061, Shaanxi, China.
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Li W, Li M, Wang H, Peng Y, Dong S, Lu Y, Wang F, Xu F, Liu L, Zhao Q. Infiltrating Immune Cells in Gastric Cancer: A Novel Predicting Model for Prognosis. J Cancer 2021; 12:965-975. [PMID: 33442396 PMCID: PMC7797666 DOI: 10.7150/jca.51079] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2020] [Accepted: 11/01/2020] [Indexed: 02/07/2023] Open
Abstract
Objective: Immune cells infiltrating has been proved to be associated with prognosis in gastric cancer (GC) by studies. This study aims to explore the prognosis value of infiltrating immune cells in gastric cancer. Methods: In our study, the CIBERSORT algorithm was used to calculate the fraction of 22 tumor-infiltrating immune cells (TIIC) in 100 normal and 300 tumor samples from the GEO cohort and 30 normal and 344 tumor samples from the TCGA cohort. Univariate and multivariate Cox regression were used to construct an immune risk score model. Multivariate cox regression was also used to validate whether our risk score model could predict prognosis in GC independently. Furthermore, the model was validated in different patient subgroups to test its independence. P<0.05 was considered statistically significant. Results: The results showed that the fraction of 3 immune cells increased in tumor tissues compared with normal tissues in both the GEO and TCGA cohort. Univariate cox regression analysis showed four cells significantly correlated with survival rate in GC (P<0.05). The immune risk score model was constructed based on the four cells through multivariate cox regression and further validated. The KM survival curve suggested that patients with high risk had poor prognosis than patients with low risk (P<0.05). ROC curve indicated the model was reliable (AUC= 0.67 in the GEO cohort, AUC = 0.65 in the TCGA cohort). Furthermore, multivariate Cox regression showed the model was an independent factor for overall survival predicting in GC (hazard ratio (HR) = 2.35, 95% confidence interval (CI) = 1.63~3.40 in the GEO cohort, HR = 2.87, 95% CI = 1.94~4.25 in the TCGA cohort). Finally, we validated the model in patient subgroups by the KM survival curve. Conclusion: In summary, tumor-infiltrating immune cells play an essential role in GC progression and affect the outcome of GC patients. The immune risk score can predict overall survival for GC independently, and high immune risk score is associated with poor prognosis.
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Affiliation(s)
- Wenjie Li
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, China
| | - Mengting Li
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, China
| | - Haizhou Wang
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, China
| | - Yanan Peng
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, China
| | - Shouquan Dong
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, China
| | - Yuanyuan Lu
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, China
| | - Fan Wang
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, China
| | - Fei Xu
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, China
| | - Lan Liu
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, China
| | - Qiu Zhao
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, China
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35
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Donlon NE, Sheppard A, Davern M, O’Connell F, Phelan JJ, Power R, Nugent T, Dinneen K, Aird J, Greene J, Nevins Selvadurai P, Bhardwaj A, Foley EK, Ravi N, Donohoe CL, Reynolds JV, Lysaght J, O’Sullivan J, Dunne MR. Linking Circulating Serum Proteins with Clinical Outcomes in Esophageal Adenocarcinoma-An Emerging Role for Chemokines. Cancers (Basel) 2020; 12:cancers12113356. [PMID: 33202734 PMCID: PMC7698106 DOI: 10.3390/cancers12113356] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 11/10/2020] [Accepted: 11/12/2020] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Cancer of the esophagus (food pipe) is an aggressive type of cancer with poor prognosis and rates are increasing. Current treatments help to prolong survival but only for a minority of patients, therefore there is an urgent need to discover why some people do not respond and to develop new and improved treatments. Newer treatments targeting the immune system show promise but the anti-tumor immune response in esophageal cancer is not well understood. This study measured levels of 54 immune markers in serum of patients with esophageal cancer and evaluated a link with patient clinical outcomes, e.g., survival time, response to treatment, and adverse events. We found that certain chemokines, proteins which control immune cell trafficking, were particularly high in patients who survived longer (CCL22 and CCL26) and responded to treatment (CCL4), suggesting the importance of immune cell movement in orchestrating an effective immune response to esophageal cancer. Abstract Esophageal adenocarcinoma (EAC) is an aggressive cancer with poor prognosis and incidence is increasing rapidly in the Western world. Multi-modal treatment has improved survival outcomes but only for a minority of patients. Currently no markers have been identified to predict treatment response. This study investigated the association between clinical outcomes and pre-treatment levels of 54 serum proteins in n = 80 patients with EAC. Low tumor regression grade (TRG), corresponding to a favorable treatment response, was linked to prolonged overall survival (OS). CCL4 was higher in patients with a favorable treatment response, while Tie2 and CRP were higher in poor responders. Elevated CCL22 and CCL26 was associated with improved OS, while elevated IL-10 showed a negative association. CCL3, CCL4, IL-1α and IL-12/IL23p40 were highest in individuals with no adverse features of tumor biology, whereas levels of Tie2 and VEGF were lowest in this cohort. CCL4 was also elevated in patients with high tumor lymphocyte infiltration. Comparison of matched pre- and post-treatment serum (n = 28) showed a large reduction in VEGFC, and a concomitant increase in other cytokines, including CCL4. These data link several serum markers with clinical outcomes, highlighting an important role for immune cell trafficking in the EAC antitumor immune response.
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Affiliation(s)
- Noel E. Donlon
- Department of Surgery, Trinity Translational Medicine Institute, Trinity College Dublin, St James’s Hospital, Dublin 8, Ireland; (N.E.D.); (A.S.); (M.D.); (F.O.); (J.J.P.); (R.P.); (T.N.); (A.B.); (E.K.F.); (N.R.); (C.L.D.); (J.V.R.); (J.L.); (J.O.)
- Trinity St James’s Cancer Institute, St James’s Hospital, Dublin 8, Ireland
| | - Andrew Sheppard
- Department of Surgery, Trinity Translational Medicine Institute, Trinity College Dublin, St James’s Hospital, Dublin 8, Ireland; (N.E.D.); (A.S.); (M.D.); (F.O.); (J.J.P.); (R.P.); (T.N.); (A.B.); (E.K.F.); (N.R.); (C.L.D.); (J.V.R.); (J.L.); (J.O.)
- Trinity St James’s Cancer Institute, St James’s Hospital, Dublin 8, Ireland
| | - Maria Davern
- Department of Surgery, Trinity Translational Medicine Institute, Trinity College Dublin, St James’s Hospital, Dublin 8, Ireland; (N.E.D.); (A.S.); (M.D.); (F.O.); (J.J.P.); (R.P.); (T.N.); (A.B.); (E.K.F.); (N.R.); (C.L.D.); (J.V.R.); (J.L.); (J.O.)
- Trinity St James’s Cancer Institute, St James’s Hospital, Dublin 8, Ireland
| | - Fiona O’Connell
- Department of Surgery, Trinity Translational Medicine Institute, Trinity College Dublin, St James’s Hospital, Dublin 8, Ireland; (N.E.D.); (A.S.); (M.D.); (F.O.); (J.J.P.); (R.P.); (T.N.); (A.B.); (E.K.F.); (N.R.); (C.L.D.); (J.V.R.); (J.L.); (J.O.)
- Trinity St James’s Cancer Institute, St James’s Hospital, Dublin 8, Ireland
| | - James J. Phelan
- Department of Surgery, Trinity Translational Medicine Institute, Trinity College Dublin, St James’s Hospital, Dublin 8, Ireland; (N.E.D.); (A.S.); (M.D.); (F.O.); (J.J.P.); (R.P.); (T.N.); (A.B.); (E.K.F.); (N.R.); (C.L.D.); (J.V.R.); (J.L.); (J.O.)
- Trinity St James’s Cancer Institute, St James’s Hospital, Dublin 8, Ireland
| | - Robert Power
- Department of Surgery, Trinity Translational Medicine Institute, Trinity College Dublin, St James’s Hospital, Dublin 8, Ireland; (N.E.D.); (A.S.); (M.D.); (F.O.); (J.J.P.); (R.P.); (T.N.); (A.B.); (E.K.F.); (N.R.); (C.L.D.); (J.V.R.); (J.L.); (J.O.)
- Trinity St James’s Cancer Institute, St James’s Hospital, Dublin 8, Ireland
| | - Timothy Nugent
- Department of Surgery, Trinity Translational Medicine Institute, Trinity College Dublin, St James’s Hospital, Dublin 8, Ireland; (N.E.D.); (A.S.); (M.D.); (F.O.); (J.J.P.); (R.P.); (T.N.); (A.B.); (E.K.F.); (N.R.); (C.L.D.); (J.V.R.); (J.L.); (J.O.)
- Trinity St James’s Cancer Institute, St James’s Hospital, Dublin 8, Ireland
| | - Kate Dinneen
- Department of Histopathology, St James’s Hospital, Dublin 8, Ireland; (K.D.); (J.A.)
| | - John Aird
- Department of Histopathology, St James’s Hospital, Dublin 8, Ireland; (K.D.); (J.A.)
| | - John Greene
- Department of Medical Oncology, St James’s Hospital, Dublin 8, Ireland; (J.G.); (P.N.S.)
| | - Paul Nevins Selvadurai
- Department of Medical Oncology, St James’s Hospital, Dublin 8, Ireland; (J.G.); (P.N.S.)
| | - Anshul Bhardwaj
- Department of Surgery, Trinity Translational Medicine Institute, Trinity College Dublin, St James’s Hospital, Dublin 8, Ireland; (N.E.D.); (A.S.); (M.D.); (F.O.); (J.J.P.); (R.P.); (T.N.); (A.B.); (E.K.F.); (N.R.); (C.L.D.); (J.V.R.); (J.L.); (J.O.)
- Trinity St James’s Cancer Institute, St James’s Hospital, Dublin 8, Ireland
| | - Emma K. Foley
- Department of Surgery, Trinity Translational Medicine Institute, Trinity College Dublin, St James’s Hospital, Dublin 8, Ireland; (N.E.D.); (A.S.); (M.D.); (F.O.); (J.J.P.); (R.P.); (T.N.); (A.B.); (E.K.F.); (N.R.); (C.L.D.); (J.V.R.); (J.L.); (J.O.)
- Trinity St James’s Cancer Institute, St James’s Hospital, Dublin 8, Ireland
| | - Narayanasamy Ravi
- Department of Surgery, Trinity Translational Medicine Institute, Trinity College Dublin, St James’s Hospital, Dublin 8, Ireland; (N.E.D.); (A.S.); (M.D.); (F.O.); (J.J.P.); (R.P.); (T.N.); (A.B.); (E.K.F.); (N.R.); (C.L.D.); (J.V.R.); (J.L.); (J.O.)
- Trinity St James’s Cancer Institute, St James’s Hospital, Dublin 8, Ireland
| | - Claire L. Donohoe
- Department of Surgery, Trinity Translational Medicine Institute, Trinity College Dublin, St James’s Hospital, Dublin 8, Ireland; (N.E.D.); (A.S.); (M.D.); (F.O.); (J.J.P.); (R.P.); (T.N.); (A.B.); (E.K.F.); (N.R.); (C.L.D.); (J.V.R.); (J.L.); (J.O.)
- Trinity St James’s Cancer Institute, St James’s Hospital, Dublin 8, Ireland
| | - John V. Reynolds
- Department of Surgery, Trinity Translational Medicine Institute, Trinity College Dublin, St James’s Hospital, Dublin 8, Ireland; (N.E.D.); (A.S.); (M.D.); (F.O.); (J.J.P.); (R.P.); (T.N.); (A.B.); (E.K.F.); (N.R.); (C.L.D.); (J.V.R.); (J.L.); (J.O.)
- Trinity St James’s Cancer Institute, St James’s Hospital, Dublin 8, Ireland
| | - Joanne Lysaght
- Department of Surgery, Trinity Translational Medicine Institute, Trinity College Dublin, St James’s Hospital, Dublin 8, Ireland; (N.E.D.); (A.S.); (M.D.); (F.O.); (J.J.P.); (R.P.); (T.N.); (A.B.); (E.K.F.); (N.R.); (C.L.D.); (J.V.R.); (J.L.); (J.O.)
- Trinity St James’s Cancer Institute, St James’s Hospital, Dublin 8, Ireland
| | - Jacintha O’Sullivan
- Department of Surgery, Trinity Translational Medicine Institute, Trinity College Dublin, St James’s Hospital, Dublin 8, Ireland; (N.E.D.); (A.S.); (M.D.); (F.O.); (J.J.P.); (R.P.); (T.N.); (A.B.); (E.K.F.); (N.R.); (C.L.D.); (J.V.R.); (J.L.); (J.O.)
- Trinity St James’s Cancer Institute, St James’s Hospital, Dublin 8, Ireland
| | - Margaret R. Dunne
- Department of Surgery, Trinity Translational Medicine Institute, Trinity College Dublin, St James’s Hospital, Dublin 8, Ireland; (N.E.D.); (A.S.); (M.D.); (F.O.); (J.J.P.); (R.P.); (T.N.); (A.B.); (E.K.F.); (N.R.); (C.L.D.); (J.V.R.); (J.L.); (J.O.)
- Trinity St James’s Cancer Institute, St James’s Hospital, Dublin 8, Ireland
- Correspondence:
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Luo T, Du Y, Duan J, Liang C, Chen G, Jiang K, Chen Y, Chen Y. Development and Validation of a Scoring System Based on 9 Glycolysis-Related Genes for Prognosis Prediction in Gastric Cancer. Technol Cancer Res Treat 2020; 19:1533033820971670. [PMID: 33161837 PMCID: PMC7658532 DOI: 10.1177/1533033820971670] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Gastric cancer is a malignant tumor with high morbidity and mortality worldwide. However, increasing evidences have revealed the correlation between the glycolysis process and tumorigenesis. This study is aim to develop a list of glycolysis-related genes for risk stratification in gastric cancer patients. We included 500 patients’ sample data from GSE62254 and GSE26942 datasets, and classified patients into training (n = 350) and testing sets (n = 150) at a ratio of 7: 3. Univariate and multivariate Cox regression analysis were performed to screen genes having prognostic value. Based on HALLMARK gene sets, we identified 9 glycolysis-related genes (BPNT1, DCN, FUT8, GMPPA, GPC3, LDHC, ME2, PLOD2, and UGP2). On the basis of risk score developed by the 9 genes, patients were classified into high- and low-risk groups. The survival analysis showed that the high-risk patients had a worse prognosis (p < 0.001). Similar finding was observed in the testing cohort and 2 independent cohorts (GSE13861 and TCGA-STAD, all p < 0.001). The multivariate Cox regression analysis showed that the risk score was an independent prognostic factor for overall survival (p < 0.001). Furthermore, we constructed a nomogram that integrated the risk score and tumor stage, age, and adjuvant chemotherapy. Through comparing the results of the receiver operating characteristic curves and decision curve analysis, we found that the nomogram had a superior predictive accuracy than conventional TNM staging system, suggesting that the risk score combined with other clinical factors (age, tumor stage, and adjuvant chemotherapy) can develop a robust prediction for survival and improve the individualized clinical decision making of the patient. In conclusion, we identified 9 glycolysis-related genes from hallmark glycolysis pathway. Based on the 9 genes, gastric cancer patients were separated into different risk groups related to survival.
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Affiliation(s)
- Tianqi Luo
- Department of Gastric Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Yufei Du
- Department of Gastric Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
- Department of Biotherapy, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Jinling Duan
- Department of Gastric Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
- Department of Experimental Research (Cancer Institute), Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Chengcai Liang
- Department of Gastric Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Guoming Chen
- Department of Gastric Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Kaiming Jiang
- Department of Gastric Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Yongming Chen
- Department of Gastric Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
- Yingbo Chen, and Yongming Chen, Dongfeng East Road 651, Guangzhou, Guangdong 510060, China. Emails: ;
| | - Yingbo Chen
- Department of Gastric Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
- Yingbo Chen, and Yongming Chen, Dongfeng East Road 651, Guangzhou, Guangdong 510060, China. Emails: ;
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Development and validation of metabolism-related gene signature in prognostic prediction of gastric cancer. Comput Struct Biotechnol J 2020; 18:3217-3229. [PMID: 33209209 PMCID: PMC7649605 DOI: 10.1016/j.csbj.2020.09.037] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Revised: 09/24/2020] [Accepted: 09/26/2020] [Indexed: 12/24/2022] Open
Abstract
Gastric cancer is one of the most common malignant tumours in the world. As one of the crucial hallmarks of cancer reprogramming of metabolism and the relevant researches have a promising application in the diagnosis treatment and prognostic prediction of malignant tumours. This study aims to identify a group of metabolism-related genes to construct a prediction model for the prognosis of gastric cancer. A large cohort of gastric cancer cases (1121 cases) from public database was included in our analysis and classified patients into training and testing cohorts at a ratio of 7: 3. After identifying a list of metabolism-related genes having prognostic value, we constructed a risk score based on metabolism-related genes using LASSO-COX method. According to the risk score, patients were divided into high- and low-risk groups. Our results revealed that high-risk patients had a significantly worse prognosis than low-risk patients in both the training (high-risk vs low-risk patients; five years overall survival: 37.2% vs 72.2%; p < 0.001) and testing cohorts (high-risk vs low-risk patients; five years overall survival: 42.9% vs 62.9%; p < 0.001). This observation was validated in the external validation cohort (high-risk vs. low-risk patients; five years overall survival: 30.2% vs 40.4%; p = 0.007). To reinforce the predictive ability of the model, we integrated risk score, age, adjuvant chemotherapy, and TNM stage into a nomogram. According to the result of receiver operating characteristic curves and decision curves analysis, we found that the nomogram score had a superior predictive ability than conventional factors, indicating that the risk score combined with clinicopathological features can develop a robust prediction for survival and improve the individualized clinical decision making of the patient. In conclusion, we identified a list of metabolic genes related to survival and developed a metabolism-based predictive model for gastric cancer. Through a series of bioinformatics and statistical analyses, the predictive ability of the model was confirmed.
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Zhang S, Zeng Z, Liu Y, Huang J, Long J, Wang Y, Peng X, Hu Z, Ouyang Y. Prognostic landscape of tumor-infiltrating immune cells and immune-related genes in the tumor microenvironment of gastric cancer. Aging (Albany NY) 2020; 12:17958-17975. [PMID: 32969836 PMCID: PMC7585095 DOI: 10.18632/aging.103519] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Accepted: 06/04/2020] [Indexed: 01/24/2023]
Abstract
The tumor microenvironment is closely related to the progression and immune escape of tumor cells. Tumor-infiltrating immune cells (TIICs) and immune-related genes (IRGs) are indispensable components of the tumor microenvironment and have been demonstrated to be highly valuable in determining the prognosis of multiple cancers. To elucidate the prognostic value of TIICs and IRGs in gastric cancer, we conducted a comprehensive analysis focusing on the abundances of 22 types of TIICs and differentially expressed IRGs based on a dataset from The Cancer Genome Atlas (TCGA). The results showed that great composition differences in TIICs and immune cell subfractions were associated with survival outcomes in different stages. Additionally, 29 hub genes were characterized from 345 differentially expressed IRGs and found to be significantly associated with survival outcomes. Then, an independent prognostic indicator based on ten IRGs was successfully constructed after multivariate adjustment for some clinical parameters. Further validation revealed that these hub IRGs could reflect the infiltration levels of immune cells. Thus, our results confirmed the clinical significance of TIICs and IRGs in gastric cancer and may establish a foundation for further exploring immune cell and gene targets for personalized treatment.
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Affiliation(s)
- Shichao Zhang
- Immune Cells and Antibody Engineering Research Center of Guizhou Province, Key Laboratory of Biology and Medical Engineering, School of Biology and Engineering/School of Basic Medical Sciences, Guizhou Medical University, Guiyang 550025, Guizhou, P.R. China
| | - Zhu Zeng
- Immune Cells and Antibody Engineering Research Center of Guizhou Province, Key Laboratory of Biology and Medical Engineering, School of Biology and Engineering/School of Basic Medical Sciences, Guizhou Medical University, Guiyang 550025, Guizhou, P.R. China,Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang 550025, Guizhou, P.R. China
| | - Yongfen Liu
- Immune Cells and Antibody Engineering Research Center of Guizhou Province, Key Laboratory of Biology and Medical Engineering, School of Biology and Engineering/School of Basic Medical Sciences, Guizhou Medical University, Guiyang 550025, Guizhou, P.R. China
| | - Jiangtao Huang
- Immune Cells and Antibody Engineering Research Center of Guizhou Province, Key Laboratory of Biology and Medical Engineering, School of Biology and Engineering/School of Basic Medical Sciences, Guizhou Medical University, Guiyang 550025, Guizhou, P.R. China
| | - Jinhua Long
- Affiliated Tumor Hospital, Guizhou Medical University, Guiyang 550004, Guizhou, P.R. China
| | - Yun Wang
- Immune Cells and Antibody Engineering Research Center of Guizhou Province, Key Laboratory of Biology and Medical Engineering, School of Biology and Engineering/School of Basic Medical Sciences, Guizhou Medical University, Guiyang 550025, Guizhou, P.R. China
| | - Xiaoyan Peng
- Immune Cells and Antibody Engineering Research Center of Guizhou Province, Key Laboratory of Biology and Medical Engineering, School of Biology and Engineering/School of Basic Medical Sciences, Guizhou Medical University, Guiyang 550025, Guizhou, P.R. China,Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang 550025, Guizhou, P.R. China
| | - Zuquan Hu
- Immune Cells and Antibody Engineering Research Center of Guizhou Province, Key Laboratory of Biology and Medical Engineering, School of Biology and Engineering/School of Basic Medical Sciences, Guizhou Medical University, Guiyang 550025, Guizhou, P.R. China,Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang 550025, Guizhou, P.R. China
| | - Yan Ouyang
- Immune Cells and Antibody Engineering Research Center of Guizhou Province, Key Laboratory of Biology and Medical Engineering, School of Biology and Engineering/School of Basic Medical Sciences, Guizhou Medical University, Guiyang 550025, Guizhou, P.R. China
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Nasr R, Shamseddine A, Mukherji D, Nassar F, Temraz S. The Crosstalk between Microbiome and Immune Response in Gastric Cancer. Int J Mol Sci 2020; 21:ijms21186586. [PMID: 32916853 PMCID: PMC7556019 DOI: 10.3390/ijms21186586] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2020] [Revised: 08/04/2020] [Accepted: 08/12/2020] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer is the end result of a complex interplay between host genetics, environmental factors, and microbial factors. The link between gut microbiome and gastric cancer has been attributed to persistent activation of the host's immune system by gut microbiota. The end result of this dysregulated interaction between host epithelium and microbes is a state of chronic inflammation. Gut bacteria can promote anti-tumor immune responses through several mechanisms. These include triggering T-cell responses to bacterial antigens that can cross-react with tumor antigens or cause tumor-specific antigen recognition; engagement of pattern recognition receptors that mediate pro-immune or anti-inflammatory effects or via small metabolites that mediate systemic effects on the host. Here we review the role of the gut microbiome including H. pylori and non-H. pylori gastric bacteria, the immune response, and immunotherapy using checkpoint inhibitors. We also review the evidence for cross talk between the gut microbiome and immune response in gastric cancer.
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Affiliation(s)
- Rihab Nasr
- Department of Anatomy, Cell Biology and Physiology, American University of Beirut Medical Center, Riad El Solh, Beirut 1107, Lebanon;
| | - Ali Shamseddine
- Department of Internal Medicine, Hematology/Oncology Division, American University of Beirut Medical Center, Riad El Solh, Beirut 1107, Lebanon; (A.S.); (D.M.); (F.N.)
| | - Deborah Mukherji
- Department of Internal Medicine, Hematology/Oncology Division, American University of Beirut Medical Center, Riad El Solh, Beirut 1107, Lebanon; (A.S.); (D.M.); (F.N.)
| | - Farah Nassar
- Department of Internal Medicine, Hematology/Oncology Division, American University of Beirut Medical Center, Riad El Solh, Beirut 1107, Lebanon; (A.S.); (D.M.); (F.N.)
| | - Sally Temraz
- Department of Internal Medicine, Hematology/Oncology Division, American University of Beirut Medical Center, Riad El Solh, Beirut 1107, Lebanon; (A.S.); (D.M.); (F.N.)
- Correspondence: ; Tel.: +961-137-4374
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Heo YJ, Lee T, Byeon SJ, Kim EJ, Shin HC, Kim B, Kang SY, Ha SY, Kim KM. Digital image analysis in pathologist-selected regions of interest predicts survival more accurately than whole-slide analysis: a direct comparison study in 153 gastric carcinomas. JOURNAL OF PATHOLOGY CLINICAL RESEARCH 2020; 7:42-51. [PMID: 32885920 PMCID: PMC7737754 DOI: 10.1002/cjp2.179] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Revised: 07/15/2020] [Accepted: 07/20/2020] [Indexed: 12/24/2022]
Abstract
Automatic quantification of biomarkers such as tumor‐infiltrating lymphocytes and PD‐L1 is one of the most studied topics in digital pathology image analysis (DIA). However, direct comparison between the DIA of a whole‐slide image (WSI) and that of regions of interest (ROIs) chosen by pathologists has not been performed. In this study, we aimed to compare the prognostic value of tumor microenvironment markers CD8 and PD‐L1, measured by DIA of WSIs and ROIs. We selected 153 primary gastric cancer tissues and stained them with CD8 and PD‐L1. All IHC slides were scanned at ×200 magnification and ratios of CD8 and PD‐L1 were measured in WSIs and ROIs from the invasive front, within the tumor, and the mucosa. Patients with high CD8 and PD‐L1 ratios showed more favorable outcomes compared to those with low ratios. Pathologist‐aided DIA predicted the survival of patients more accurately than WSI analysis (CD8, p = 0.025 versus p = 0.068; PD‐L1, p = 0.008 versus p = 0.2). Although a high density of CD8+ T cells at the invasive front correlated best with patient survival, CD8 ratio in the mucosa could also predict patient outcome. In conclusion, CD8 and PD‐L1 ratios measured by pathologist‐aided DIA predicted survival more accurately than WSI analyses and ROIs at the invasive front correlated best with patient outcome.
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Affiliation(s)
- You Jeong Heo
- The Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Taebum Lee
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.,Department of Pathology, Chonnam National University Medical School, Hwasun Hospital, Hwasun-gun, Republic of Korea
| | - Sun-Ju Byeon
- Department of Pathology, Hallym University Dongtan Sacred Heart Hospital, Hwaseong-si, Republic of Korea.,Center of Companion Diagnostics, Samsung Medical Center, Seoul, Republic of Korea
| | - Eun Ji Kim
- Center of Companion Diagnostics, Samsung Medical Center, Seoul, Republic of Korea
| | - Hyeong Chan Shin
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.,Center of Companion Diagnostics, Samsung Medical Center, Seoul, Republic of Korea
| | - Binnari Kim
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.,Center of Companion Diagnostics, Samsung Medical Center, Seoul, Republic of Korea
| | - So Young Kang
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Sang Yun Ha
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Kyoung-Mee Kim
- The Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.,Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.,Center of Companion Diagnostics, Samsung Medical Center, Seoul, Republic of Korea
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Zhang S, Liu W, Hu B, Wang P, Lv X, Chen S, Shao Z. Prognostic Significance of Tumor-Infiltrating Natural Killer Cells in Solid Tumors: A Systematic Review and Meta-Analysis. Front Immunol 2020; 11:1242. [PMID: 32714321 PMCID: PMC7343909 DOI: 10.3389/fimmu.2020.01242] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2020] [Accepted: 05/18/2020] [Indexed: 12/19/2022] Open
Abstract
Background: Tumor-infiltrating natural killer (NK) cells (TINKs) are crucial immune cells in tumor defense, and might be related to tumor prognosis. However, the results were discrepant among different studies. The present meta-analysis was performed to comprehensively assess the prognostic value of NK cell markers in solid tumor tissues. Methods: PubMed, Web of Science, and EMBASE were searched to identify original researches reporting the prognostic significance of TINKs in solid tumors. NK cell markers CD56, CD57, NKp30, and NKp46 were included in the analysis. The hazard ratios (HRs) and 95% confidence intervals (CIs) of pooled overall survival (OS), disease-free survival (DFS), metastasis-free survival (MFS), progression-free survival (PFS), and recurrence-free survival (RFS) were calculated by STATA software 14.0 to assess the prognostic significance. Results : Of the 56 included studies, there were 18 studies on CD56, 31 studies on CD57, 1 study on NKp30, and 7 studies on NKp46. High levels of CD56, CD57, NKp30, and NKp46 were significantly correlated with better OS of patients with solid malignancies (HR = 0.473, 95%CI: 0.315–0.710, p < 0.001; HR = 0.484, 95%CI: 0.380–0.616, p < 0.001; HR = 0.34, 95%CI: 0.14–0.80, p = 0.014; HR = 0.622, 95%CI: 0.470–0.821, p < 0.001, respectively). Our results also revealed that CD56, CD57, and NKp46 could act as independent prognostic predictors for favorable OS (HR = 0.372, 95%CI: 0.261–0.531, p < 0.001; HR = 0.525, 95%CI: 0.346–0.797, p = 0.003; HR = 0.559, 95%CI: 0.385–0.812, p = 0.002, respectively). Conclusions : Our results indicated that high levels of NK cell markers in solid tumor tissues could predict favorable prognosis for solid tumor patients.
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Affiliation(s)
- Shuo Zhang
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Weijian Liu
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Binwu Hu
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Peng Wang
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiao Lv
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Songfeng Chen
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zengwu Shao
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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42
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Zhu X, Xie X, Zhao Q, Zhang L, Li C, Zhao D. Potential Prognostic Value and Mechanism of Stromal-Immune Signature in Tumor Microenvironment for Stomach Adenocarcinoma. BIOMED RESEARCH INTERNATIONAL 2020; 2020:4673153. [PMID: 32685487 PMCID: PMC7335387 DOI: 10.1155/2020/4673153] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Accepted: 05/22/2020] [Indexed: 02/07/2023]
Abstract
Stomach adenocarcinoma (STAD) is one of the most common malignancies. But the molecular mechanism is unknown. In this study, we downloaded the transcriptional profiles and clinical data of 344 STAD and 30 normal samples from The Cancer Genome Atlas (TCGA) database. Stromal and immune scores of STAD were calculated by the Estimation of Stromal and Immune cells in Malignant Tumor tissues using Expression data (ESTIMATE) algorithm, and association of stromal/immune scores with tumor differentiation/T/N/M stage and survival was investigated. The differentially expressed genes (DEGs) between high and low score groups (based on media) were identified, and prognostic genes over-/underexpressed in both STAD and stromal/immune signature were retrieved. Furthermore, proportions of 22 infiltrating immune cells for the cohort from TCGA were estimated by the Cell-type Identification By Estimating Relative Subsets Of RNA Transcripts (CIBERSORT) algorithm, and association of 22 immune cells with tumor differentiation/T/N/M stage and survival was investigated. Next, coexpression analysis of 22 immune cells and intersection genes over-/underexpressed in both STAD and stromal signature was conducted. We found high stromal and immune scores and macrophage infiltration predicting poor tumor differentiation and severe local invasion, obtained a list of prognostic genes based on stromal-immune signature, and explored the interaction of collagen, chemokines such as CXCL9, CXCL10, and CXCL11, and macrophage through coexpression analysis and may provide novel prognostic biomarkers and immunotherapeutic targets for STAD.
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Affiliation(s)
- Xinying Zhu
- Department of Gastroenterology, Second Hospital of Hebei Medical University, Shijiazhuang, 050000 Hebei Province, China
- Department of Gastroenterology, Third Hospital of Hebei Medical University, Shijiazhuang 050051, Hebei Province, China
| | - Xiaoli Xie
- Department of Gastroenterology, Second Hospital of Hebei Medical University, Shijiazhuang, 050000 Hebei Province, China
| | - Qingchao Zhao
- Department of Gastroenterology, Second Hospital of Baoding, Baoding, 071051 Hebei Province, China
| | - Lixian Zhang
- Department of Gastroenterology, Second Hospital of Hebei Medical University, Shijiazhuang, 050000 Hebei Province, China
| | - Changjuan Li
- Department of Gastroenterology, Second Hospital of Hebei Medical University, Shijiazhuang, 050000 Hebei Province, China
| | - Dongqiang Zhao
- Department of Gastroenterology, Second Hospital of Hebei Medical University, Shijiazhuang, 050000 Hebei Province, China
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43
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Chen J, Chen JG, Sun B, Wu JH, Du CY. Integrative analysis of immune microenvironment-related CeRNA regulatory axis in gastric cancer. MATHEMATICAL BIOSCIENCES AND ENGINEERING : MBE 2020; 17:3953-3971. [PMID: 32987562 DOI: 10.3934/mbe.2020219] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
This study aimed to identify significant immune microenvironment-related competing endogenous RNA (CeRNA) regulatory axis in gastric cancer (GC). Analysis of differentially expressed mRNAs (DEmRNAs), miRNAs (DEmiRNAs), and lncRNAs (DElncRNAs) was performed for the microarray datasets. After abundance analysis of immune cell's infiltration, immune-related mRNAs and lncRNAs were obtained. Meanwhile, according to the Pearson correlation coefficient between immune-related mRNAs and lncRNAs, the co-expression mRNA-lncRNA pairs were screened. Furthermore, the target genes of co-existance miRNAs were predicted, and miRNA-lncRNA pairs were identified. Finally, the lncRNA-miRNA and miRNA-mRNA relationship regulated by the same miRNA was screened. Combining with the co-expression relationship between lncRNA and mRNA, the CeRNA network was constructed. In abundance analysis of immune cell's infiltration, a total of eight immune cells were obtained, in addition, 83 immune-related DElncRNAs and 705 immune-related DEmRNAs were screened. KEGG pathway enrichment analysis showed that these mRNAs were mainly involved in PI3K-Akt signaling pathway and human papillomavirus infection, while lncRNA were relevant to gastric acid secretion. A total of 25 miRNAs were significantly associated with immune-related mRNAs, such as hsa-miR-148a-3p, hsa-miR-17-5p, and hsa-miR-25-3p. From the mRNA-miRNA-lncRNA CeRNA network, we observed that AC104389.28─miR-17-5─SMAD5 axis and LINC01133─miR-17-5p─PBLD axis played a crucial role in the development of GC. Furthermore, resting memory CD4 T cells and plasma cells were closely associated with the pathogenesis of GC, and these immune cells might be affected by the key genes. The present study identified key genes that associated with immune microenvironment in GC, providing potential molecular targets for immunotherapy of GC.
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Affiliation(s)
- Jie Chen
- Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China
| | - Jing Gui Chen
- Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China
| | - Bo Sun
- Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China
| | - Jiang Hong Wu
- Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China
| | - Chun Yan Du
- Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China
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Mao S, Li Y, Lu Z, Che Y, Huang J, Lei Y, Wang Y, Wang X, Liu C, Zheng S, Li N, Li J, Sun N, He J. Systematic profiling of immune signatures identifies prognostic predictors in lung adenocarcinoma. Cell Oncol (Dordr) 2020; 43:681-694. [PMID: 32462608 DOI: 10.1007/s13402-020-00515-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/03/2020] [Indexed: 02/06/2023] Open
Abstract
PURPOSE Lung adenocarcinoma (LUAD) is the predominant subtype of lung cancer, with increasing evidence showing clinical benefits of immunotherapy. However, a lack of integrated profiles of complex LUAD immune microenvironments hampers the application of immunotherapy, resulting in limited eligible patient populations as well as drug resistance problems. Here, we aimed to systematically profile the immune signatures of LUADs and to assess the role of the immune microenvironment in patient outcome. METHODS We systematically profiled the immune signatures of LUADs deposited in the TCGA and GEO databases using a total of 730 immune-related genes. Differential expression analysis was used to identify dysregulated genes. Univariate Cox analysis followed by robust likelihood-based survival analysis and multivariate Cox analysis were applied to construct an immune-related prognostic model. RESULTS We found that differentially expressed immune genes were mainly enriched in immune cell proliferation, migration, activation and the NF-κB and TNF signaling pathways. The 10-immune gene predictive model that we constructed could differentiate LUAD patients with different overall survival times in several datasets, with areas under the curve (AUCs) of 0.67, 0.69, 0.72 and 0.74. LUAD patients with high- or low-risk scores exhibited distinct immune cell compositions, which may explain the prognostic significance of our model. CONCLUSIONS Our results add to the current knowledge of immune processes in LUADs and underscore the critical role of the immune microenvironment in LUAD patient outcome.
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Affiliation(s)
- Shuangshuang Mao
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Yuan Li
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Zhiliang Lu
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Yun Che
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Jianbing Huang
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Yuanyuan Lei
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Yalong Wang
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Xinfeng Wang
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Chengming Liu
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Sufei Zheng
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Ning Li
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Jiagen Li
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Nan Sun
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
| | - Jie He
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
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Däster S, Eppenberger-Castori S, Mele V, Schäfer HM, Schmid L, Weixler B, Soysal SD, Droeser RA, Spagnoli GC, Kettelhack C, Oertli D, Terracciano L, Tornillo L, von Holzen U. Low Expression of Programmed Death 1 (PD-1), PD-1 Ligand 1 (PD-L1), and Low CD8+ T Lymphocyte Infiltration Identify a Subgroup of Patients With Gastric and Esophageal Adenocarcinoma With Severe Prognosis. Front Med (Lausanne) 2020; 7:144. [PMID: 32411711 PMCID: PMC7199486 DOI: 10.3389/fmed.2020.00144] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2019] [Accepted: 04/03/2020] [Indexed: 12/21/2022] Open
Abstract
Prognosis of gastric and esophageal cancer is poor and treatment improvements are needed. Programmed cell death 1 receptor (PD-1) interaction with its ligand PD-L1 in tumor micro-environment promotes immune tolerance and blocking monoclonal antibodies have entered clinical practice. However, clinical significance of PD-1 and PD-L1 expression in gastric and esophageal adenocarcinomas, particularly in non-Asian patients, is still unclear. Three tissue microarrays including 190 clinically annotated esophageal (n = 31) and gastric (n = 159) adenocarcinomas and 58 paired mucosa specimens, were stained with PD-1, PD-L1, and CD8-specific reagents in indirect immunohistochemistry assays. PD-L1 expression was detectable in 23.2% of cancer specimens. High PD-1 expression was detectable in 37.3% of cases and high CD8+ infiltration in 76%. PD-L1 and high PD1 expression significantly correlated with each other (rs = 0.404, P < 0.0001) and both significantly correlated with CD8+ infiltration (rs = 0.435, P = 0.0003, and rs = 0.444; P = 0.0004, respectively). CD8+ lymphocyte infiltration correlated with improved survival in univariate (P = 0.009), but not multivariate analysis. Most interestingly, multivariate analysis and Kaplan-Meier curves indicate that combined low PD-1/PD-L1 expression and low CD8+ lymphocyte infiltration significantly correlate with poor prognosis. Our data document the clinical significance of a microenvironmental signature including PD-1/PD-L1 expression and CD8+ lymphocyte infiltration in gastric and esophageal adenocarcinomas and contribute to identify a patients' subset requiring more aggressive peri-operative treatments.
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Affiliation(s)
- Silvio Däster
- Department of Surgery, University Hospital Basel, Basel, Switzerland
| | | | - Valentina Mele
- Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Hannah M Schäfer
- Department of Surgery, University Hospital Basel, Basel, Switzerland
| | - Lukas Schmid
- Department of Surgery, University Hospital Basel, Basel, Switzerland
| | - Benjamin Weixler
- Department of Surgery, University Hospital Basel, Basel, Switzerland
| | - Savas D Soysal
- Department of Surgery, University Hospital Basel, Basel, Switzerland
| | - Raoul A Droeser
- Department of Surgery, University Hospital Basel, Basel, Switzerland
| | - Giulio C Spagnoli
- National Research Council, Institute of Translational Pharmacology, Rome, Italy
| | | | - Daniel Oertli
- Department of Surgery, University Hospital Basel, Basel, Switzerland
| | - Luigi Terracciano
- Division of Molecular Pathology, Institute of Pathology, University Hospital Basel, Basel, Switzerland
| | - Luigi Tornillo
- Division of Molecular Pathology, Institute of Pathology, University Hospital Basel, Basel, Switzerland
| | - Urs von Holzen
- Department of Surgery, University Hospital Basel, Basel, Switzerland.,Harper Cancer Research Institute, Indiana University School of Medicine South Bend, South Bend, IN, United States.,Goshen Center for Cancer Care, Goshen, IN, United States
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46
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Immuno-oncology: developing integrated approaches toward clinical success of biologics and small-molecule modulators. FUTURE DRUG DISCOVERY 2020. [DOI: 10.4155/fdd-2019-0035] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Immuno-oncology (IO) therapy is an exciting emerging pillar of cancer treatment that embraces the concept of modulating the immune system to recognize tumor cells and target them for destruction by either harnessing the effects of the immune system or preventing the evasion of tumor cells from therapeutic targeting. However, our immune system is constantly in a delicate balance between under-performing immune cells failing to manage pathogens, infections or cancer and over-performing immune cells potentially causing autoimmune disorders or cytokine release storms. Over the last 30 years, IO has progressed considerably with approvals for the use of various IO therapeutics including vaccines, cytokines, tumor-directed monoclonal antibodies, immune checkpoint inhibitors as well as chimeric antigen receptor (CAR) and T-cell receptor (TCR) engineered T-cell therapies.
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47
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Zhang N, Wang D, Duan Y, Ayarick VA, Cao M, Wang Y, Zhang G, Wang Y. The special immune microenvironment of tumor budding and its impact on prognosis in gastric adenocarcinoma. Pathol Res Pract 2020; 216:152926. [PMID: 32327282 DOI: 10.1016/j.prp.2020.152926] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Revised: 02/23/2020] [Accepted: 03/14/2020] [Indexed: 12/30/2022]
Abstract
Recent studies showed that the tumor-infiltrating lymphocytes (TILs) are not randomly distributed, but organized to accumulate more or less densely in different regions within tumors, which have provoked new thoughts on cancer management. In this study we explored the characteristics of tumor immunemicroenvironment (TIME) for the tumor budding (TB) and lymphocytes in patients with gastric adenocarcinoma (GAC) as well as their prognostic significance. The TILs around the TB at the invasive margin were assessed by double-immunohistochemistry staining for the CD8, FOXP3, OX40 and GrB phenotypes. Results showed that there was a negative correlation between the density of TB and TILs in the budding area, tumor stroma and parenchyma. And the number of TILs around the TB was evidently reduced, compared with TILs in the non-budding region (P < 0.001). Additionally, the number of TILs in turn changed from non-budding area CD8+>FOXP3+>OX40+> GrB + T cells to FOXP3+>CD8+>OX40 + T > GrB + T cells in budding area. Survival rate was significantly lower in patients who had a higher density of TB (P < 0.001) and a lower density of TILs (P = 0.013). We concluded that TB was surrounded by a weak immune surveillance and immunosuppressive response supported the spatial heterogeneity in the TIME of gastric adenocarcinomas. The regional heterogeneity should be attached importance for identifying the influence of the TIME on cancer development and evolution.
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Affiliation(s)
- Nana Zhang
- Institute for Cancer Research, School of Basic Medical Science, Health Science Center of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
| | - Depu Wang
- Department of Science and Technology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
| | - Yixin Duan
- Institute for Cancer Research, School of Basic Medical Science, Health Science Center of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
| | - Vivian Adiila Ayarick
- Institute for Cancer Research, School of Basic Medical Science, Health Science Center of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
| | - Meng Cao
- Institute for Cancer Research, School of Basic Medical Science, Health Science Center of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
| | - Ying Wang
- Institute for Cancer Research, School of Basic Medical Science, Health Science Center of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
| | - Guanjun Zhang
- Department of Pathology, The First Affiliated Hospital of Xi'an Jiaotong University, Xian, Shaanxi, 710061, China.
| | - Yili Wang
- Institute for Cancer Research, School of Basic Medical Science, Health Science Center of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China.
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Ji L, Qian W, Gui L, Ji Z, Yin P, Lin GN, Wang Y, Ma B, Gao WQ. Blockade of β-Catenin-Induced CCL28 Suppresses Gastric Cancer Progression via Inhibition of Treg Cell Infiltration. Cancer Res 2020; 80:2004-2016. [PMID: 32156780 DOI: 10.1158/0008-5472.can-19-3074] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Revised: 01/07/2020] [Accepted: 03/05/2020] [Indexed: 11/16/2022]
Abstract
Dysregulation of Wnt/β-catenin signaling is frequently observed in human gastric cancer. Elucidation of the tumor immune microenvironment is essential for understanding tumorigenesis and for the development of immunotherapeutic strategies. However, it remains unclear how β-catenin signaling regulates the tumor immune microenvironment in the stomach. Here, we identify CCL28 as a direct transcriptional target gene of β-catenin/T-cell factor (TCF). Protein levels of β-catenin and CCL28 positively correlated in human gastric adenocarcinoma. β-Catenin-activated CCL28 recruited regulatory T (Treg) cells in a transwell migration assay. In a clinically relevant mouse gastric cancer model established by Helicobacter (H.) felis infection and N-methyl-N-nitrosourea (MNU) treatment, inhibition of β-catenin/TCF activity by a pharmacologic inhibitor iCRT14 suppressed CCL28 expression and Treg cell infiltration in the stomach. Moreover, an anti-CCL28 antibody attenuated Treg cell infiltration and tumor progression in H. felis/MNU mouse models. Diphtheria toxin-induced Treg cell ablation restrained gastric cancer progression in H. felis/MNU-treated DEREG (Foxp3-DTR) mice, clarifying the tumor-promoting role of Treg cells. Thus, the β-catenin-CCL28-Treg cell axis may serve as an important mechanism for immunosuppression of the stomach tumor microenvironment. Our findings reveal an immunoregulatory role of β-catenin signaling in stomach tumors and highlight the therapeutic potential of CCL28 blockade for the treatment of gastric cancer. SIGNIFICANCE: These findings demonstrate an immunosuppressive role of tumor-intrinsic β-catenin signaling and the therapeutic potential of CCL28 blockade in gastric cancer.
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Affiliation(s)
- Lu Ji
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Clinical Stem Cell Research Center, Renji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.,Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
| | - Wei Qian
- School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Liming Gui
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Clinical Stem Cell Research Center, Renji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.,Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
| | - Zhongzhong Ji
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Clinical Stem Cell Research Center, Renji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.,Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
| | - Pan Yin
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Clinical Stem Cell Research Center, Renji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.,Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
| | - Guan Ning Lin
- School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - You Wang
- Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Bin Ma
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Clinical Stem Cell Research Center, Renji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China. .,Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
| | - Wei-Qiang Gao
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Clinical Stem Cell Research Center, Renji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China. .,Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
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49
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Wang X, Jing W, Lin SH. Is there value of tumor stromal infiltrating lymphocytes for response assessment to chemoradiation in esophageal squamous cell carcinoma? ANNALS OF TRANSLATIONAL MEDICINE 2020; 7:S283. [PMID: 32016002 DOI: 10.21037/atm.2019.11.82] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Affiliation(s)
- Xin Wang
- Department of Radiation Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin 300000, China
| | - Wang Jing
- Department of Radiation Oncology, Shandong Cancer Institute, Jinan 250000, China
| | - Steven H Lin
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
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50
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Yin SP, Gao Y, Xie XS, Xu DD, Riabov V, Du WD. Accumulation of stabilin-1 positive macrophages in the early stage of gastric cancer is associated with short cumulative survival. Oncol Lett 2020; 19:2404-2412. [PMID: 32194740 PMCID: PMC7039161 DOI: 10.3892/ol.2020.11310] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2019] [Accepted: 12/05/2019] [Indexed: 01/01/2023] Open
Abstract
The scavenger receptor stabilin-1 has been reported to be expressed by tumor-associated macrophages (TAMs) and to facilitate tumor growth and metastasis in mouse models of breast carcinoma and melanoma. However, to the best of our knowledge, its expression and association with prognosis in human gastric cancer has not been evaluated. The present study investigated the expression of stabilin-1 and its association with clinicopathological parameters in patients with gastric cancer. The expression of stabilin-1 was evaluated by immunohistochemical staining of gastric cancer tissue samples of 371 Chinese patients with primary gastric adenocarcinoma. Confocal laser scanning microscopy was used to determine the cellular source of stabilin-1 in the gastric cancer tissues using anti-CD68, anti-CD163, anti-stabilin-1 and anti-secreted protein acidic and rich in cysteine antibodies. A higher number of stabilin-1-positive cells were observed in the cancer tissues of primary gastric adenocarcinoma compared with adjacent non-cancerous tissues of primary gastric adenocarcinoma (P<0.001); the majority of stabilin-1-positve cells were CD68+/CD163+ macrophages. Poorly-differentiated gastric cancer tissue had fewer stabilin-1-positive cells compared with medium- and well-differentiated gastric cancer (P=0.030). A higher number of stabilin-1-positive cells were found in the early Tumor-Node-Metastasis (TNM) stage (TNM I stage) of primary gastric adenocarcinoma (P=0.038) compared with TNM stage IV. For patients with TNM stage I disease, a higher number of stabilin-1-positive TAMs was associated with shorter cumulative survival (P<0.05). Overall, stabilin-1 was found to be expressed by CD68+ TAMs in human gastric cancer. The high expression of stabilin-1 in TNM stage I disease was associated with poor patient survival, indicating the clinical significance of stabilin-1 in gastric cancer.
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Affiliation(s)
- Shui-Ping Yin
- Department of Pathology, Anhui Medical University, Hefei, Anhui 230032, P.R. China.,Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Yi Gao
- Department of Pathology, Anhui Medical University, Hefei, Anhui 230032, P.R. China.,Department of Biology, School of Life Sciences, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Xu-Shi Xie
- Department of Pathology, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Dan-Dan Xu
- Department of Oncology, The Fourth Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230012, P.R. China
| | - Vladimir Riabov
- Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Heidelberg University, D-68167 Mannheim, Germany
| | - Wei-Dong Du
- Department of Pathology, Anhui Medical University, Hefei, Anhui 230032, P.R. China.,Department of Biology, School of Life Sciences, Anhui Medical University, Hefei, Anhui 230032, P.R. China
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