|
1
|
Deng Q, Li W, Huang Y, Wang H, Zhou X, Guan Z, Cheng B, Wang Y. Immunolipid magnetic bead-based circulating tumor cell sorting: a novel approach for pathological staging of colorectal cancer. Front Oncol 2025; 14:1531972. [PMID: 39927117 PMCID: PMC11803635 DOI: 10.3389/fonc.2024.1531972] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Accepted: 12/31/2024] [Indexed: 02/11/2025] Open
Abstract
Objective This study aimed to assess whether circulating tumor cells (CTCs) from colorectal cancer (CRC) could be used as an alternative to tissue samples for genetic mutation testing, overcoming the challenge of difficult tumor tissue acquisition. Methods We developed an immunolipid magnetic bead (IMB) system modified with antibodies against epithelial cell adhesion molecule (EpCAM) and vimentin to efficiently separate CTCs. We prepared EpCAM-modified IMBs (Ep-IMBs) and vimentin-modified IMBs (Vi-IMBs). The separation efficiency of the system was evaluated via in vitro experiments and by capturing and counting CTCs in blood samples from 23 CRC patients and 20 healthy controls. Hotspot mutations in patient tissue samples were identified via next-generation sequencing (NGS), whereas mutations in blood CTCs were detected via Sanger sequencing. The concordance between hotspot mutations in tumor tissue and blood CTCs was analyzed. Results The CTC sorting system exhibited good dispersion, stability, and low cytotoxicity, with a specificity of 90.54% and a sensitivity of 89.07%. CRC patients had an average of 8.39 CTCs per 7.5 mL of blood, whereas healthy controls had 0.09 per 7.5 mL of blood. The consistency of gene mutations was as follows: TP53 (91.31%), PIK3CA (76.00%), KRAS (85.36%), BRAF (51.00%), APC (65.67%), and EGFR (74.00%), with an overall gene mutation consistency of 85.06%. Conclusion Our CTC sorting system, which is based on Ep-IMBs and Vi-IMBs, effectively captures CTCs in the peripheral blood of CRC patients and enables clinical hotspot gene mutation testing via these enriched CTCs. This system partially solves the problem of difficult tumor tissue sample collection and provides a reference for gene mutation testing in early diagnosis, therapeutic efficacy evaluation, prognosis assessment, and minimal metastasis detection in CRC patients, showing significant potential for clinical application, especially in targeted therapy gene testing for CRC.
Collapse
Affiliation(s)
| | | | | | | | | | | | | | - Yao Wang
- Department of Gastrointestinal Surgery, Zhongshan People’s Hospital, Zhongshan, Guangdong, China
| |
Collapse
|
|
2
|
Xu L, Liu J, An Y, Zhou L, Sun H, Xu Z, Wang D, Liang Z, Xu C, Wang B, Li W. Glycolysis-related genes predict prognosis and indicate immune microenvironment features in gastric cancer. BMC Cancer 2024; 24:979. [PMID: 39118022 PMCID: PMC11313097 DOI: 10.1186/s12885-024-12747-z] [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: 03/19/2024] [Accepted: 08/01/2024] [Indexed: 08/10/2024] Open
Abstract
BACKGROUND Gastric cancer (GC) is a major contributor to cancer-related mortality. Glycolysis plays a pivotal role in tumor microenvironment (TME) reprogramming. In this research, the functions of glycolysis-associated genes (GRGs) were evaluated to predict the outcome and reveal the characteristics of the immune microenvironment in individuals with stomach cancer. METHODS The Cancer Genome Atlas (TCGA)-stomach adenocarcinoma (STAD) cohort provided gene expression and clinical data for gastric cancer (GC) patients, which were further authenticated using datasets sourced from the Gene Expression Omnibus (GEO). By referencing the Molecular Signatures Database (MSigDB), a total of 326 GRGs were pinpointed. The various subtypes of GC were outlined through consensus clustering, derived from the expression patterns of these GRGs. Utilizing multivariate Cox regression analysis, a multigene risk score model was formulated. Both the CIBERSORT and ESTIMATE algorithms played a pivotal role in assessing the immune microenvironment. To delve into the biological functions of the key genes, wound healing, transwell invasion, and MTT assays were conducted. RESULTS Based on the expression patterns of GRGs, patients were categorized into two distinct groups: the metabolic subtype, designated as cluster A, and the immune subtype, labeled as cluster B. Patients belonging to cluster B exhibited a poorer prognosis. A prognostic risk score model, formulated upon the expression levels of six key GRGs - ME1, PLOD2, NUP50, CXCR4, SLC35A3, and SRD35A3 - emerged as a viable tool for predicting patient outcomes. The downregulation of CXCR4 notably diminished the glycolytic capacity of gastric cancer (GC) cells, alongside their migratory, invasive, and proliferative capabilities. Intriguingly, despite the adverse prognostic implications associated with both the immune subtype (cluster B) and the high-risk cohort, these groups exhibited a favorable immune microenvironment coupled with elevated expression of immune checkpoint genes. Our investigations revealed a positive correlation between high CXCR4 expression and low ME1 expression with the infiltration of CD8+ T cells, as well as an enhanced responsiveness to treatment with an anti-PD-1 immune checkpoint inhibitor. CONCLUSIONS In this study, we discovered that the expression profiles of GRGs hold the potential to forecast the prognosis of gastric cancer (GC) patients, thereby possibly aiding in clinical treatment decision-making.
Collapse
Affiliation(s)
- Lu Xu
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China
| | - Jin Liu
- Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China
| | - Yuanqing An
- Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China
| | - Lei Zhou
- Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China
| | - Hui Sun
- Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China
| | - Zhen Xu
- Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China
| | - Deqiang Wang
- Department of Oncology, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, China
| | - Zhanwen Liang
- Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China
| | - Caihua Xu
- Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China.
| | - Bingyi Wang
- Department of Oncology, Changshu No.1 People's Hospital, Suzhou, 215500, China.
| | - Wei Li
- Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China.
| |
Collapse
|
|
3
|
Li W, Zhang X, Yang Y, Lin J, Zhou K, Sun R, Dang C, Diao D. Circulating tumor cells are a good predictor of tumor recurrence in clinical patients with gastric cancer. Sci Rep 2024; 14:12758. [PMID: 38830909 PMCID: PMC11148116 DOI: 10.1038/s41598-024-63305-3] [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: 02/28/2024] [Accepted: 05/27/2024] [Indexed: 06/05/2024] Open
Abstract
Circulating tumor cells (CTCs) as a liquid biopsy have great potential in clinical applications and basic cancer research, but their clinical use in gastric cancer remains unclear. This study investigated whether CTCs could be used as a potential prognosis predictor in patients with gastric cancer. A total of 120 patients with pathologically confirmed gastric cancer were enrolled from January 1, 2015, to December 1, 2019. All patients were initially diagnosed without previous treatment, and then the number of CTCs was detected using the NEimFISH method before radical surgical resection. Regular follow-up was performed in all patients, and the correlations between the number of CTCs and clinical endpoints, such as disease-free survival (DFS) and overall survival (OS), were evaluated. The univariate and multivariate hazard ratios were calculated using the Cox proportional hazard model. Based on the number of CTCs, we defined CTCs ≥ 2 per 7.5 mL of whole blood as the positive group and CTCs < 2 as the negative group. Among the 120 patients who underwent CTC detection before surgery, the rate of CTC-positive patients was 64.17% (77/120) of which stage I and II patients accounted for 22.50% and stage III patients accounted for 41.67% (P = 0.014). By detecting CTCs before surgery and at the time of recurrence, the number of CTCs tends to increase concomitantly with disease progression (median: 2 VS 5 per 7.5 mL). Multivariate analysis showed that age (HR, 0.259; 95% CI, 0.101-0.662; P = 0.005), D-dimer (HR, 3.146; 95% CI, 1.169-8.461; P = 0.023), and lymph node metastasis (HR, 0.207; 95% CI, 0.0071-0.603; P = 0.004) were factors correlated with CTCs. In addition, the median follow-up of all the patients was 38.0 months (range of 28-80 months); the DFS in CTC-positive patients was significantly shorter than that of the CTC-negative patients, and a significant difference was found based on the Cox proportional hazard regression model analysis (44.52 ± 2.83 m vs. 74.99 ± 2.78 m, HR = 4.550, P = 0.018). The OS was shorter in the CTC-positive group than in the CTC-negative group before the operation, but the result was not significant based on the Cox proportional hazard regression model analysis (47.58 ± 2.46 m vs. 70.68 ± 3.53 m, HR = 2.261, P = 0.083). The number of CTCs tends to increase concomitantly with disease progression. In addition, the detection of CTCs was an independent predictor of shorter DFS in gastric cancer. However, the relationship between CTCs and OS needs to be determined in future studies.
Collapse
Affiliation(s)
- Wenxing Li
- Department of Surgical Oncology, Xi'an Jiaotong University Medical College First Affiliated Hospital, 277 West Yanta Road, Xi'an, 710061, Shaanxi, China
| | - Xin Zhang
- Department of Surgical Oncology, Xi'an Jiaotong University Medical College First Affiliated Hospital, 277 West Yanta Road, Xi'an, 710061, Shaanxi, China
| | - Yanqi Yang
- Department of Pathology, School of Basic Medical Sciences, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Jinhe Lin
- Department of Surgical Oncology, Xi'an Jiaotong University Medical College First Affiliated Hospital, 277 West Yanta Road, Xi'an, 710061, Shaanxi, China
| | - Kai Zhou
- Department of Surgical Oncology, Xi'an Jiaotong University Medical College First Affiliated Hospital, 277 West Yanta Road, Xi'an, 710061, Shaanxi, China
| | - Ruifang Sun
- Department of Pathology, School of Basic Medical Sciences, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Chengxue Dang
- Department of Surgical Oncology, Xi'an Jiaotong University Medical College First Affiliated Hospital, 277 West Yanta Road, Xi'an, 710061, Shaanxi, China.
| | - Dongmei Diao
- Department of Surgical Oncology, Xi'an Jiaotong University Medical College First Affiliated Hospital, 277 West Yanta Road, Xi'an, 710061, Shaanxi, China.
| |
Collapse
|
|
4
|
Díaz del Arco C, Fernández Aceñero MJ, Ortega Medina L. Liquid biopsy for gastric cancer: Techniques, applications, and future directions. World J Gastroenterol 2024; 30:1680-1705. [PMID: 38617733 PMCID: PMC11008373 DOI: 10.3748/wjg.v30.i12.1680] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 02/01/2024] [Accepted: 03/08/2024] [Indexed: 03/28/2024] Open
Abstract
After the study of circulating tumor cells in blood through liquid biopsy (LB), this technique has evolved to encompass the analysis of multiple materials originating from the tumor, such as nucleic acids, extracellular vesicles, tumor-educated platelets, and other metabolites. Additionally, research has extended to include the examination of samples other than blood or plasma, such as saliva, gastric juice, urine, or stool. LB techniques are diverse, intricate, and variable. They must be highly sensitive, and pre-analytical, patient, and tumor-related factors significantly influence the detection threshold, diagnostic method selection, and potential results. Consequently, the implementation of LB in clinical practice still faces several challenges. The potential applications of LB range from early cancer detection to guiding targeted therapy or immunotherapy in both early and advanced cancer cases, monitoring treatment response, early identification of relapses, or assessing patient risk. On the other hand, gastric cancer (GC) is a disease often diagnosed at advanced stages. Despite recent advances in molecular understanding, the currently available treatment options have not substantially improved the prognosis for many of these patients. The application of LB in GC could be highly valuable as a non-invasive method for early diagnosis and for enhancing the management and outcomes of these patients. In this comprehensive review, from a pathologist's perspective, we provide an overview of the main options available in LB, delve into the fundamental principles of the most studied techniques, explore the potential utility of LB application in the context of GC, and address the obstacles that need to be overcome in the future to make this innovative technique a game-changer in cancer diagnosis and treatment within clinical practice.
Collapse
Affiliation(s)
- Cristina Díaz del Arco
- Department of Surgical Pathology, Health Research Institute of the Hospital Clínico San Carlos, Hospital Clínico San Carlos, Madrid 28040, Spain
- Department of Legal Medicine, Psychiatry and Pathology, Universidad Complutense de Madrid, Madrid 28040, Spain
| | - M Jesús Fernández Aceñero
- Department of Surgical Pathology, Health Research Institute of the Hospital Clínico San Carlos, Hospital Clínico San Carlos, Madrid 28040, Spain
- Department of Legal Medicine, Psychiatry and Pathology, Universidad Complutense de Madrid, Madrid 28040, Spain
| | - Luis Ortega Medina
- Department of Surgical Pathology, Health Research Institute of the Hospital Clínico San Carlos, Hospital Clínico San Carlos, Madrid 28040, Spain
- Department of Legal Medicine, Psychiatry and Pathology, Universidad Complutense de Madrid, Madrid 28040, Spain
| |
Collapse
|
|
5
|
Hakami ZH. Biomarker discovery and validation for gastrointestinal tumors: A comprehensive review of colorectal, gastric, and liver cancers. Pathol Res Pract 2024; 255:155216. [PMID: 38401376 DOI: 10.1016/j.prp.2024.155216] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2023] [Revised: 02/07/2024] [Accepted: 02/15/2024] [Indexed: 02/26/2024]
Abstract
Gastrointestinal (GI) malignancies, encompassing gastric, hepatic, colonic, and rectal cancers, are prevalent forms of cancer globally and contribute substantially to cancer-related mortality. Although there have been improvements in methods for diagnosing and treating GI cancers, the chances of survival for these types of cancers are still extremely low. According to the World Cancer Research International Fund's most recent figures, stomach cancer was responsible for roughly one million deaths worldwide in 2020. This emphasizes the importance of developing more effective tools for detecting, diagnosing, and predicting the outcome of these cancers at an early stage. Biomarkers, quantitative indications of biological processes or disease states, have emerged as promising techniques for enhancing the diagnosis and prognosis of GI malignancies. Recently, there has been a considerable endeavor to discover and authenticate biomarkers for various GI cancers by the utilization of diverse methodologies, including genomics, proteomics, and metabolomics. This review provides a thorough examination of the current state of biomarker research in the field of gastrointestinal malignancies, with a specific emphasis on colorectal, stomach, and liver cancers. A thorough literature search was performed on prominent databases such as PubMed, Scopus, and Web of Science to find pertinent papers published until November, 2023 for the purpose of compiling this review. The diverse categories of biomarkers, encompassing genetic, epigenetic, and protein-based biomarkers, and their potential utility in the fields of diagnosis, prognosis, and treatment selection, are explored. Recent progress in identifying and confirming biomarkers, as well as the obstacles that persist in employing biomarkers in clinical settings are emphasized. The utilization of biomarkers in GI cancers has significant potential in enhancing patient outcomes. Ongoing research is expected to uncover more efficient biomarkers for the diagnosis and prognosis of these cancers.
Collapse
Affiliation(s)
- Zaki H Hakami
- Department of Medical Laboratory Technology, Faculty of Applied Medical Science, Jazan University, Jazan 45142, Saudi Arabia.
| |
Collapse
|
|
6
|
Xia F, Zhang Q, Ndhlovu E, Zhang M, Zou Y. A Novel Nomogram to Predict Resectable Gastric Cancer Based on Preoperative Circulating Tumor Cell. Clin Transl Gastroenterol 2024; 15:e00561. [PMID: 36727697 PMCID: PMC10887436 DOI: 10.14309/ctg.0000000000000561] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Accepted: 11/21/2022] [Indexed: 02/03/2023] Open
Abstract
INTRODUCTION Circulating tumor cells (CTCs) have been suggested to have an important prognostic role in gastrointestinal tumors. We developed a preoperative CTC-based nomogram to predict the prognosis of patients with resectable gastric cancer after surgery and established a risk stratification system based on the nomogram. METHODS From January 2012 to June 2017, we screened 258 patients with gastric cancer treated with surgery from one center as the training cohort and 133 patients with gastric cancer treated with surgery from another as the validation cohort, screened prognostic factors for the training cohort using univariate and multivariate Cox risk proportional models, created predictive overall survival (OS) and a recurrence-free survival (RFS) nomogram, and plotted the receiver operating characteristic curve and calibration curve for this nomogram in the training and validation cohorts. Risk score stratification was performed according to the nomogram, and OS curves were plotted for the low, medium, and high-risk groups using the Kaplan-Meier method. RESULTS The CTC positivity rate was 78.5% in all patients. CTC, TNM stage, and Ki-67 were the prognostic factors affecting OS and RFS after gastric cancer surgery. The nomogram consisted of these 3 variables. In the training group, the area under the curve of the nomogram for OS at 1, 3, and 5 years was 0.918, 0.829, and 0.813, respectively, and the area under the curve for RFS was 0.900, 0884, and 0.839, respectively. There was a statistically significant difference in OS among the low, medium, and high-risk groups according to the risk stratification system constructed from nomogram scores ( P < 0.001). DISCUSSION Two nomograms based on preoperative CTC were established to predict OS and RFS after resectable gastric cancer. The 2 nomograms had good discrimination and calibration and significant stratification ability of the risk stratification system established according to them.
Collapse
Affiliation(s)
- Feng Xia
- Department of Hepatic Surgery, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Qiao Zhang
- Zhongshan People's Hospital Affiliated to Guangdong Medical University, Guangdong, China
| | - Elijah Ndhlovu
- Department of Hepatic Surgery, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Mingyu Zhang
- Department of Digestive Medicine, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
| | - You Zou
- Gastrointestinal Surgery Center, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei, China
| |
Collapse
|
|
7
|
Wu X, Shi M, Lian Y, Zhang H. Exosomal circRNAs as promising liquid biopsy biomarkers for glioma. Front Immunol 2023; 14:1039084. [PMID: 37122733 PMCID: PMC10140329 DOI: 10.3389/fimmu.2023.1039084] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Accepted: 03/30/2023] [Indexed: 05/02/2023] Open
Abstract
Liquid biopsy strategies enable the noninvasive detection of changes in the levels of circulating biomarkers in body fluid samples, providing an opportunity to diagnose, dynamically monitor, and treat a range of diseases, including cancers. Glioma is among the most common forms of intracranial malignancy, and affected patients exhibit poor prognostic outcomes. As such, diagnosing and treating this disease in its early stages is critical for optimal patient outcomes. Exosomal circular RNAs (circRNAs) are involved in both the onset and progression of glioma. Both the roles of exosomes and methods for their detection have received much attention in recent years and the detection of exosomal circRNAs by liquid biopsy has significant potential for monitoring dynamic changes in glioma. The present review provides an overview of the circulating liquid biopsy biomarkers associated with this cancer type and the potential application of exosomal circRNAs as tools to guide the diagnosis, treatment, and prognostic evaluation of glioma patients during disease progression.
Collapse
Affiliation(s)
- Xiaoke Wu
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Mengmeng Shi
- Department of Ophthalmology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Yajun Lian
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- *Correspondence: Haifeng Zhang, ; Yajun Lian,
| | - Haifeng Zhang
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- *Correspondence: Haifeng Zhang, ; Yajun Lian,
| |
Collapse
|
|
8
|
Validation of the DNA Methylation Landscape of TFF1/TFF2 in Gastric Cancer. Cancers (Basel) 2022; 14:cancers14225474. [PMID: 36428568 PMCID: PMC9688599 DOI: 10.3390/cancers14225474] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Revised: 10/25/2022] [Accepted: 11/02/2022] [Indexed: 11/09/2022] Open
Abstract
As one of the most frequently occurring tumor types, the increasing incidence of gastric cancer (GC) has been observed in the past decades. The recent studies have illustrated that epigenetic modifications mediated by DNA methyltransferases (DNMTs) are the major epigenetic hallmark in GC progression. Nowadays, DNA methylation was considered to be necessary for inducing the silence of tumor suppressor genes (TSGs). As an important group of peptides, the TFF family has been confirmed to function as a TSG in various kinds of cancers. However, whether TFFs could be modified by DNA methylation in gastric cancer remains unknown. Here, we initially screened out two transcriptional sequencing profiles about GC from Gene Expression Omnibus (GEO) database. The lower expression levels of TFF1 and TFF2 were observed in GC tumor tissues as compared to those in normal tissues. Additionally, utilizing the Kaplan-Meier analysis, the expressions of TFF1 and TFF2 were identified to be associated with the prognosis of GC patients. Subsequently, the integrative analysis was performed to estimate the DNA methylation level of each site in TFF1/TFF2 CpG islands. Importantly, our findings indicated that hyper-methylation of cg01886855 and cg26403416 were separately responsible for the downregulation of TFF1 and TFF2 in GC samples. In addition, utilizing the experiments in vitro, we demonstrated that TFF1/TFF2 could suppress the proliferation of GC cells. Based on these results, we suspected that TFF1/TFF2 could potentially act as the putative tumor suppressor in GC, and these two TFFs were of great value for predicting the overall survival (OS) status in the gastric cancer cohort. Totally, our findings revealed a potential therapeutic method for targeting the TFFs for the treatment of GC.
Collapse
|
|
9
|
Removal of Circulating Tumor Cells from Blood Samples of Cancer Patients Using Highly Magnetic Nanoparticles: A Translational Research Project. Pharmaceutics 2022; 14:pharmaceutics14071397. [PMID: 35890293 PMCID: PMC9315588 DOI: 10.3390/pharmaceutics14071397] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 06/27/2022] [Accepted: 06/28/2022] [Indexed: 12/15/2022] Open
Abstract
The count of circulating tumor cells (CTCs) has been associated with a worse prognosis in different types of cancer. Perioperatively, CTCs detach due to mechanical forces. Diagnostic tools exist to detect and isolate CTCs, but no therapeutic technique is currently available to remove CTCs in vivo from unprocessed blood. The aim of this study was to design and test new magnetic nanoparticles to purify whole blood from CTCs. Novel magnetic carbon-coated cobalt (C/Co) nanoparticles conjugated with anti-epithelial cell adhesion molecule (EpCAM) antibodies were synthesized, and their antifouling and separation properties were determined. The newly developed C/Co nanoparticles showed excellent separation and antifouling properties. They efficiently removed tumor cells that were added to healthy subjects’ blood samples, through an anti-EpCAM antibody interaction. The nanoparticles did not interact with other blood components, such as lymphocytes or the coagulation system. In blood samples of carcinoma patients suffering from metastatic disease, on average, ≥68% of CTCs were removed. These nanoparticles could prompt the development of a blood purification technology, such as a dialysis-like device, to perioperatively remove CTCs from the blood of cancer patients in vivo and potentially improve their prognosis.
Collapse
|
|
10
|
Negishi R, Yamakawa H, Kobayashi T, Horikawa M, Shimoyama T, Koizumi F, Sawada T, Oboki K, Omuro Y, Funasaka C, Kageyama A, Kanemasa Y, Tanaka T, Matsunaga T, Yoshino T. Transcriptomic profiling of single circulating tumor cells provides insight into human metastatic gastric cancer. Commun Biol 2022; 5:20. [PMID: 35017627 PMCID: PMC8752828 DOI: 10.1038/s42003-021-02937-x] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Accepted: 12/01/2021] [Indexed: 12/24/2022] Open
Abstract
Transcriptome analysis of circulating tumor cells (CTCs), which migrate into blood vessels from primary tumor tissues, at the single-cell level offers critical insights into the biology of metastasis and contributes to drug discovery. However, transcriptome analysis of single CTCs has only been reported for a limited number of cancer types, such as multiple myeloma, breast, hepatocellular, and prostate cancer. Herein, we report the transcriptome analysis of gastric cancer single-CTCs. We utilized an antigen-independent strategy for CTC isolation from metastatic gastric cancer patients involving a size-dependent recovery of CTCs and a single cell isolation technique. The transcriptomic profile of single-CTCs revealed that a majority of gastric CTCs had undergone epithelial-mesenchymal transition (EMT), and indicated the contribution of platelet adhesion toward EMT progression and acquisition of chemoresistance. Taken together, this study serves to employ CTC characterization to elucidate the mechanisms of chemoresistance and metastasis in gastric cancer.
Collapse
Affiliation(s)
- Ryo Negishi
- Division of Biotechnology and Life science, Institute of Engineering, Tokyo University of Agriculture and Technology, 2-24-16, Naka-cho, Koganei, Tokyo, 184-8588, Japan
| | - Hitomi Yamakawa
- Division of Biotechnology and Life science, Institute of Engineering, Tokyo University of Agriculture and Technology, 2-24-16, Naka-cho, Koganei, Tokyo, 184-8588, Japan
| | - Takeru Kobayashi
- Division of Biotechnology and Life science, Institute of Engineering, Tokyo University of Agriculture and Technology, 2-24-16, Naka-cho, Koganei, Tokyo, 184-8588, Japan
| | - Mayuko Horikawa
- Division of Biotechnology and Life science, Institute of Engineering, Tokyo University of Agriculture and Technology, 2-24-16, Naka-cho, Koganei, Tokyo, 184-8588, Japan
| | - Tatsu Shimoyama
- Department of Medical Oncology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan
| | - Fumiaki Koizumi
- Department of Laboratory Medicine, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan
| | - Takeshi Sawada
- Department of Medical Oncology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan
| | - Keisuke Oboki
- Center for Medical Research Cooperation, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Japan
| | - Yasushi Omuro
- Department of Medical Oncology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan
| | - Chikako Funasaka
- Department of Medical Oncology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan
| | - Akihiko Kageyama
- Department of Medical Oncology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan
| | - Yusuke Kanemasa
- Department of Medical Oncology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan
| | - Tsuyoshi Tanaka
- Division of Biotechnology and Life science, Institute of Engineering, Tokyo University of Agriculture and Technology, 2-24-16, Naka-cho, Koganei, Tokyo, 184-8588, Japan
| | - Tadashi Matsunaga
- Division of Biotechnology and Life science, Institute of Engineering, Tokyo University of Agriculture and Technology, 2-24-16, Naka-cho, Koganei, Tokyo, 184-8588, Japan
| | - Tomoko Yoshino
- Division of Biotechnology and Life science, Institute of Engineering, Tokyo University of Agriculture and Technology, 2-24-16, Naka-cho, Koganei, Tokyo, 184-8588, Japan.
| |
Collapse
|
|
11
|
Qiu Y, Zhang X, Deng X, Zhang R, Cai Z, Zhang Z, Liu H. Circulating tumor cell-associated white blood cell cluster is associated with poor survival of patients with gastric cancer following radical gastrectomy. Eur J Surg Oncol 2021; 48:1039-1045. [PMID: 34836729 DOI: 10.1016/j.ejso.2021.11.115] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Revised: 09/29/2021] [Accepted: 11/16/2021] [Indexed: 12/20/2022] Open
Abstract
INTRODUCTION The prognostic implication of circulating tumor cell (CTC) -associated white blood cell clusters (CTC-WBC clusters) in patients with gastric cancer (GC) after radical gastrectomy is not well defined. METHODS The prognostic value of the CTC-WBC clusters was evaluated retrospectively in an independent cohort of GC patients with radical gastrectomy from Nanfang Hospital, Southern Medical University, China, between March 1, 2018, and September 31, 2019. The cohort was grouped into two groups: CTC-WBC group and CTC group. The CTC-WBC clusters and CTCs in blood were detected by technology of Canapatrol™ CTC filtration system. The Kaplan-Meier method was used to generate survival curve and compare the disease-free survival and OS. Cox regression model was used for multivariate analyses. RESULTS Two hundred and seventeen patients were included for analyses, 29 patients presenting CTC-WBC clusters positive (CTC-WBC group) and 188 patients presenting exclusively CTCs (CTC group). Depth of tumor invasion was statistically different between two groups (P = 0.043), and the other clinicopathological features between the two groups were similar. Kaplan-Meier analysis showed that positive CTC-WBC cluster patients had significantly shorter OS than patients with exclusively CTC (P = 0.037). Cox regression analysis revealed that CTC-WBC cluster was an independent factor (Hazard Ratio = 2.553, 95% Confidence Interval: 1.008-6.465, P = 0.048) for OS after adjustment of age, gender, number of CTCs, type of CTCs, and tumor stage. CONCLUSION The presence of CTC-WBC clusters is associated with poor OS in the GC patients after radical surgery regardless of tumor stage. Our data suggest alternative prognostic model needs to be further investigated.
Collapse
Affiliation(s)
- Yaopeng Qiu
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Xinxin Zhang
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Xiangqian Deng
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Renyi Zhang
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Zhen Cai
- Laboratory Medicine Center, Nanfang Hospital, Southern Medical University, Guangzhou, China.
| | - Zhenzhan Zhang
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
| | - Hao Liu
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
| |
Collapse
|
|
12
|
Jiang SS, Mao CG, Feng YG, Jiang B, Tao SL, Tan QY, Deng B. Circulating tumor cells with epithelial-mesenchymal transition markers as potential biomarkers for the diagnosis of lung cancer. World J Clin Cases 2021; 9:2721-2730. [PMID: 33969055 PMCID: PMC8058682 DOI: 10.12998/wjcc.v9.i12.2721] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 02/19/2021] [Accepted: 03/05/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Circulating tumor cells (CTCs) can be clustered into three subtypes according to epithelial-mesenchymal transition (EMT) markers: CTCs with epithelial markers (E-CTCs), CTCs with mesenchymal markers (M-CTCs), and CTCs with both markers (E&M-CTCs). CTC detection has clinical implications in the diagnosis of lung cancer (LC).
AIM To clarify the diagnostic value of CTCs categorized by EMT markers in LC.
METHODS The study included 106 patients with lung adenocarcinoma, including 42 ground-glass opacities (GGO) and 64 solid lesions, who underwent surgery between July 2015 and December 2019. Eleven patients with benign tumors and seventeen healthy controls were included. CTCs in peripheral blood and associated EMT markers were detected preoperatively using the CanPatrolTM technique. The diagnostic power of CTCs for discriminating LC cases from controls was analyzed by the receiver operating characteristic (ROC) curve. The CytoploRare technique was used in 20 cases and 18 controls for validation, and Kappa values were calculated to evaluate consistency between techniques.
RESULTS Of the 106 LC cases, 94 (89.6%) had at least one CTC. CTCs were detectable in 35 (83.3%) of 42 GGO cases. Total CTCs and E&M-CTCs were significantly more frequent in LC cases than in benign or healthy controls. The proportion of M-CTCs plus E&M-CTCs increased gradually from healthy controls, to benign controls, to LC cases. The area under the ROC curve of total CTCs and E&M-CTCs was > 0.8 and > 10.75, respectively. The combined sensitivity of total-CTCs and E&M-CTCs was 85.85% for LC patients (80.95% for GGO patients) and the specificity was 78.57%. The Kappa value was 0.415, indicating relative consistency between CanPatrolTM and CytoploRare.
CONCLUSION CTC detection is valuable for distinguishing LC from controls, and particularly E&M-CTC detection warrants further study.
Collapse
Affiliation(s)
- Sha-Sha Jiang
- Department of Thoracic Surgery, Institute of Surgery Research, Daping Hospital, Army Medical University, Chongqing 400042, China
| | - Chun-Guo Mao
- Department of Thoracic Surgery, Institute of Surgery Research, Daping Hospital, Army Medical University, Chongqing 400042, China
| | - Yong-Geng Feng
- Department of Thoracic Surgery, Institute of Surgery Research, Daping Hospital, Army Medical University, Chongqing 400042, China
| | - Bin Jiang
- Department of Thoracic Surgery, Institute of Surgery Research, Daping Hospital, Army Medical University, Chongqing 400042, China
| | - Shao-Lin Tao
- Department of Thoracic Surgery, Institute of Surgery Research, Daping Hospital, Army Medical University, Chongqing 400042, China
| | - Qun-You Tan
- Department of Thoracic Surgery, Institute of Surgery Research, Daping Hospital, Army Medical University, Chongqing 400042, China
| | - Bo Deng
- Department of Thoracic Surgery, Institute of Surgery Research, Daping Hospital, Army Medical University, Chongqing 400042, China
| |
Collapse
|
|
13
|
Huang ZB, Zhang HT, Yu B, Yu DH. Cell-free DNA as a liquid biopsy for early detection of gastric cancer. Oncol Lett 2021; 21:3. [PMID: 33240409 PMCID: PMC7681206 DOI: 10.3892/ol.2020.12264] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Accepted: 09/17/2020] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) is one of the most common malignant tumors with poor prognosis worldwide, mainly due to the lack of suitable modalities for population-based screening and early detection of this disease. Therefore, novel and less invasive tests with improved clinical utility are urgently required. The remarkable advances in genomics and proteomics, along with emerging new technologies for highly sensitive detection of genetic alterations, have shown the potential to map the genomic makeup of a tumor in liquid biopsies, in order to assist with early detection and clinical management. The present review summarize the current status in the identification and development of cell-free DNA (cfDNA)-based biomarkers in GC, and also discusses their potential utility and the technical challenges in developing practical cfDNA-based liquid biopsy for early detection of GC.
Collapse
Affiliation(s)
- Zheng-Bin Huang
- Department of Surgery, Hanchuan Renmin Hospital, Hanchuan, Hubei 431600, P.R. China
| | - Hai-Tao Zhang
- Department of Gastrointestinal Surgery, The Second People's Hospital of Shenzhen, Shenzhen, Guangdong 518037, P.R. China
| | - Benjamin Yu
- Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - De-Hua Yu
- Shenzhen USK Bioscience Co., Ltd., Shenzhen, Guangdong 518110, P.R. China
| |
Collapse
|
|
14
|
Yang F, Ma J, Wan J, Ha W, Fang C, Lu H, Zhang W. Epithelial-mesenchymal transition of circulating tumor cells in prostate cancer is promoted by survivin. J Int Med Res 2020; 48:300060519892395. [PMID: 31948306 PMCID: PMC7254165 DOI: 10.1177/0300060519892395] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Objective Recent studies demonstrated that circulating tumor cells (CTCs) contribute to the metastasis of prostate cancer. Survivin knockout could inhibit epithelial-mesenchymal transition (EMT) and suppress several metastatic tumors. In this study, we examined the potential involvement of survivin in EMT in CTCs. Methods CTCs were isolated from the peripheral blood of 100 patients with prostate cancer as EpCAM+/CD45− cells via FACS sorting and identified by immunofluorescence staining of prostate-specific antigen (PSA). CTCs and DU145 cells were transfected with survivin siRNA. Then, the levels of survivin, E-cadherin, and vimentin in CTCs and DU145 cells were detected via immunofluorescence staining, and the invasiveness of CTCs and DU145 cells was examined using a Transwell chamber. Results The results revealed the abundant expression of PSA in the cytoplasm of CTCs. Transfection of survivin siRNA significantly decreased the levels of survivin and vimentin in CTCs and DU145, whereas that of E-cadherin was significantly increased, suggesting survivin plays an important role in EMT of CTCs. In addition, survivin siRNA significantly inhibited the invasiveness of CTCs and DU145 cells. Conclusions Survivin plays an important role in EMT of CTCs in prostate cancer, which might mediate the metastasis and invasion of prostate cancer.
Collapse
Affiliation(s)
- Faying Yang
- Department of Urology, Zhangye People's Hospital Affiliated to Hexi University, Zhangye 734000, P. R. China
| | - Jianhua Ma
- Department of Urology, The First Hospital of LanZhou University, LanZhou 730000, P. R. China
| | - Jianghou Wan
- Department of Urology, The First Hospital of LanZhou University, LanZhou 730000, P. R. China
| | - Wuhua Ha
- Department of Urology, The First Hospital of LanZhou University, LanZhou 730000, P. R. China
| | - Cheng Fang
- Department of Urology, The First Hospital of LanZhou University, LanZhou 730000, P. R. China
| | - Huaiquan Lu
- Department of Urology, The First Hospital of LanZhou University, LanZhou 730000, P. R. China
| | | |
Collapse
|
|
15
|
Guo X, Li M. LINC01089 is a tumor-suppressive lncRNA in gastric cancer and it regulates miR-27a-3p/TET1 axis. Cancer Cell Int 2020; 20:507. [PMID: 33088215 PMCID: PMC7568383 DOI: 10.1186/s12935-020-01561-9] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Accepted: 09/17/2020] [Indexed: 12/21/2022] Open
Abstract
Background Gastric cancer (GC) is one of the most common malignancies around the world. Recently, the role of long non-coding RNA (lncRNA) in cancer biology has become a hot research topic. This work aimed to explore the biological function and underlying mechanism of LINC01089 in GC. Methods Quantitative real-time polymerase chain reaction (qRT-PCR) was employed to investigate the expression of LINC01089 in GC tissues and cells. The relationship between the expression level of LINC01089 and the clinicopathological parameters of GC was assessed. Cell models of LINC01089 overexpression, LINC01089 knockdown, miR-27a-3p overexpression, and miR-27a-3p inhibition were established by transfection. CCK-8 assay, BrdU assay, and Transwell assay were utilized to investigate the malignant biological behaviors of GC cell lines after transfection. Dual luciferase activity reporter assay, Pearson’s correlation analysis, and Western blot were utilized to the regulatory relationships among LINC01089, miR-27a-3p and tet methylcytosine dioxygenase 1 (TET1). Result LINC01089 down-regulation was observed in GC tissues and cell lines. Low expression level of LINC01089 in GC tissues was markedly linked to larger tumor size, higher T stage, as well as lymphatic metastasis of the patients. Functional experiments implied that LINC01089 overexpression impeded the proliferation, migration, as well as invasion of GC cells, whereas LINC01089 knockdown promoted the above malignant phenotypes. Additionally, up-regulation of miR-27a-3p was also observed in GC tissues. Functional experiments also showed that, miR-27a-3p overexpression boosted the malignant biological behaviors of GC cells; on the contrast, these phenotypes were impeded by miR-27a-3p inhibition. Moreover, LINC01089 interacted with and repressed miR-27a-3p, and miR-27a-3p antagonized the impact of LINC01089 on GC cells. Additionally, TET1 was verified as a target gene of miR-27a-3p, and could be positively regulated by LINC01089. Conclusion LINC01089 impedes the proliferation, migration, and invasion of GC cells by adsorbing miR-27a-3p and up-regulating the expression of TET1.
Collapse
Affiliation(s)
- Xufeng Guo
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, 430000 Hubei China
| | - Ming Li
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Zhangzhidong Road, Wuchang District, Wuhan, 430000 Hubei China
| |
Collapse
|
|
16
|
Intraoperative blood loss as an independent prognostic factor for curative resection after neoadjuvant chemotherapy for gastric cancer: a single-center retrospective cohort study. Surg Today 2020; 51:293-302. [PMID: 32839832 DOI: 10.1007/s00595-020-02114-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2020] [Accepted: 07/14/2020] [Indexed: 12/28/2022]
Abstract
PURPOSE Surgery-induced factors such as postoperative infectious complications (PICs) and intraoperative blood loss (IBL) have a negative impact on the survival of patients undergoing surgery for gastric cancer. A recent study showed that neoadjuvant chemotherapy (NAC) could reduce the negative impact of PICs; hence, we conducted the present study to investigate if NAC can also reduce the negative prognostic impact of IBL. METHODS We reviewed 115 gastric cancer patients treated with NAC and radical gastrectomy. The cut-off for IBL predicting the long-term survival was assessed by a receiver operating characteristic curve. The Cox proportional hazard model was used to evaluate the association between patient characteristics including IBL, overall survival, and disease-free survival. RESULTS The cut-off for IBL was set at 990 ml. Twenty-six patients had excessive IBL exceeding 990 ml (22.6%) and PICs developed in 33 patients (28.7%). The body mass index, IBL, ypT, and ypN were significant independent prognostic predictors, but PICs were not. CONCLUSION NAC did not decrease the risk induced by excessive IBL. The prophylactic effect of NAC on surgery-induced risk was inconsistent.
Collapse
|
|
17
|
Lv Q, Xia Q, Li J, Wang Z. Allicin suppresses growth and metastasis of gastric carcinoma: the key role of microRNA-383-5p-mediated inhibition of ERBB4 signaling. Biosci Biotechnol Biochem 2020; 84:1997-2004. [PMID: 32597323 DOI: 10.1080/09168451.2020.1780903] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Allicin is a natural product suppressing the progression of gastric carcinoma (GC). In the current study, the mechanism underlying the anti-GC effect of allicin was explored by focusing on the role of miR-383-5p/ERBB4 signaling. Two GC cell lines were treated with allicin and the effects on viability, apoptosis, migration, invasion, and miR-383-5p/ERBB4 activity in the cells were assessed. The interaction between allicin and miR-383-5p was further explored by inhibiting the miR-383-5p level. Allicin suppressed cell viability and induced apoptosis in both GC cell lines. The compound also inhibited migration and invasion of GC cells, which was associated with the up-regulation miR-383-5p and down-regulation of ERBB4. The inhibition of miR-383-5p by specific inhibitor blocked the anti-GC effect of allicin. Our results demonstrated that allicin contributed to the suppressed growth and metastasis potentials in GC cell lines. The effect was accompanied by an increased level of miR-383-5p and subsequent inhibition of ERBB4.
Collapse
Affiliation(s)
- Qing Lv
- Department of Gastrointestinal Surgery, Wuhan Union Hospital , Wuhan, China
| | - Qinghua Xia
- Department of Gastrointestinal Surgery, Wuhan Union Hospital , Wuhan, China
| | - Jiang Li
- Department of Gastrointestinal Surgery, Wuhan Union Hospital , Wuhan, China
| | - Zhiyong Wang
- Department of Gastrointestinal Surgery, Wuhan Union Hospital , Wuhan, China
| |
Collapse
|
|
18
|
Thanh Huong P, Gurshaney S, Thanh Binh N, Gia Pham A, Hoang Nguyen H, Thanh Nguyen X, Pham-The H, Tran PT, Truong Vu K, Xuan Duong N, Pelucchi C, La Vecchia C, Boffetta P, Nguyen HD, Luu HN. Emerging Role of Circulating Tumor Cells in Gastric Cancer. Cancers (Basel) 2020; 12:E695. [PMID: 32183503 PMCID: PMC7140068 DOI: 10.3390/cancers12030695] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2020] [Revised: 03/11/2020] [Accepted: 03/13/2020] [Indexed: 02/07/2023] Open
Abstract
With over 1 million incidence cases and more than 780,000 deaths in 2018, gastric cancer (GC) was ranked as the 5th most common cancer and the 3rd leading cause of cancer deaths worldwide. Though several biomarkers, including carcinoembryonic antigen (CEA), cancer antigen 19-9 (CA19-9), and cancer antigen 72-4 (CA72-4), have been identified, their diagnostic accuracies were modest. Circulating tumor cells (CTCs), cells derived from tumors and present in body fluids, have recently emerged as promising biomarkers, diagnostically and prognostically, of cancers, including GC. In this review, we present the landscape of CTCs from migration, to the presence in circulation, biologic properties, and morphologic heterogeneities. We evaluated clinical implications of CTCs in GC patients, including diagnosis, prognosis, and therapeutic management, as well as their application in immunotherapy. On the one hand, major challenges in using CTCs in GC were analyzed, from the differences of cut-off values of CTC positivity, to techniques used for sampling, storage conditions, and CTC molecular markers, as well as the unavailability of relevant enrichment and detection techniques. On the other hand, we discussed future perspectives of using CTCs in GC management and research, including the use of circulating tumor microembolies; of CTC checkpoint blockade in immunotherapy; and of organoid models. Despite the fact that there are remaining challenges in techniques, CTCs have potential as novel biomarkers and/or a non-invasive method for diagnostics, prognostics, and treatment monitoring of GC, particularly in the era of precision medicine.
Collapse
Affiliation(s)
- Phung Thanh Huong
- Department of Biochemistry, Hanoi University of Pharmacy, Hanoi 10000, Vietnam;
| | - Sanjeev Gurshaney
- Cancer Division, Burnett School of Biomedical Science, College of Medicine, University of Central Florida, Orlando, FL 32827, USA;
| | - Nguyen Thanh Binh
- Department of Pharmaceutical Management and Economics, Hanoi University of Pharmacy, Hanoi 10000, Vietnam;
| | - Anh Gia Pham
- Department of Surgical Oncology, Viet-Duc University Hospital, Hanoi 10000, Vietnam; (A.G.P.); (H.H.N.); (X.T.N.)
| | - Huy Hoang Nguyen
- Department of Surgical Oncology, Viet-Duc University Hospital, Hanoi 10000, Vietnam; (A.G.P.); (H.H.N.); (X.T.N.)
| | - Xuan Thanh Nguyen
- Department of Surgical Oncology, Viet-Duc University Hospital, Hanoi 10000, Vietnam; (A.G.P.); (H.H.N.); (X.T.N.)
| | - Hai Pham-The
- Department of Pharmaceutical Chemistry, Hanoi University of Pharmacy, Hanoi 10000, Vietnam; (H.P.-T.); (P.-T.T.)
| | - Phuong-Thao Tran
- Department of Pharmaceutical Chemistry, Hanoi University of Pharmacy, Hanoi 10000, Vietnam; (H.P.-T.); (P.-T.T.)
| | - Khanh Truong Vu
- Department of Gastroenterology, Bach Mai Hospital, Hanoi 10000, Vietnam;
| | | | - Claudio Pelucchi
- Department of Clinical, Sciences and Community Health, University of Milan, 20133 Milan, Italy; (C.P.); (C.L.V.)
| | - Carlo La Vecchia
- Department of Clinical, Sciences and Community Health, University of Milan, 20133 Milan, Italy; (C.P.); (C.L.V.)
| | - Paolo Boffetta
- Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute, Division of Hematology and Medical Oncology, New York, NY 10029, USA;
| | - Hung D. Nguyen
- Cancer Division, Burnett School of Biomedical Science, College of Medicine, University of Central Florida, Orlando, FL 32827, USA;
| | - Hung N. Luu
- Department of Epidemiology, University of Pittsburg Graduate School of Public Health, Pittsburg, PA 15261, USA
- Division of Cancer Control and Population Sciences, UPMC Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, PA 15232, USA
| |
Collapse
|
|
19
|
Mensah SA, Nersesyan AA, Harding IC, Lee CI, Tan X, Banerjee S, Niedre M, Torchilin VP, Ebong EE. Flow-regulated endothelial glycocalyx determines metastatic cancer cell activity. FASEB J 2020; 34:6166-6184. [PMID: 32167209 DOI: 10.1096/fj.201901920r] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Revised: 01/30/2020] [Accepted: 02/22/2020] [Indexed: 12/14/2022]
Abstract
Cancer metastasis and secondary tumor initiation largely depend on circulating tumor cell (CTC) and vascular endothelial cell (EC) interactions by incompletely understood mechanisms. Endothelial glycocalyx (GCX) dysfunction may play a significant role in this process. GCX structure depends on vascular flow patterns, which are irregular in tumor environments. This work presents evidence that disturbed flow (DF) induces GCX degradation, leading to CTC homing to the endothelium, a first step in secondary tumor formation. A 2-fold greater attachment of CTCs to human ECs was found to occur under DF conditions, compared to uniform flow (UF) conditions. These results corresponded to an approximately 50% decrease in wheat germ agglutinin (WGA)-labeled components of the GCX under DF conditions, vs UF conditions, with undifferentiated levels of CTC-recruiting E-selectin under DF vs UF conditions. Confirming the role of the GCX, neuraminidase induced the degradation of WGA-labeled GCX under UF cell culture conditions or in Balb/C mice and led to an over 2-fold increase in CTC attachment to ECs or Balb/C mouse lungs, respectively, compared to untreated conditions. These experiments confirm that flow-induced GCX degradation can enable metastatic CTC arrest. This work, therefore, provides new insight into pathways of secondary tumor formation.
Collapse
Affiliation(s)
- Solomon A Mensah
- Department of Bioengineering, Northeastern University, Boston, MA, USA
| | - Alina A Nersesyan
- Department of Bioengineering, Northeastern University, Boston, MA, USA
| | - Ian C Harding
- Department of Bioengineering, Northeastern University, Boston, MA, USA
| | - Claire I Lee
- Department of Bioengineering, Northeastern University, Boston, MA, USA
| | - Xuefei Tan
- Department of Electrical and Computer Engineering, Northeastern University, Boston, MA, USA
| | - Selina Banerjee
- Department of Chemical Engineering, Northeastern University, Boston, MA, USA
| | - Mark Niedre
- Department of Bioengineering, Northeastern University, Boston, MA, USA.,Department of Electrical and Computer Engineering, Northeastern University, Boston, MA, USA
| | | | - Eno E Ebong
- Department of Bioengineering, Northeastern University, Boston, MA, USA.,Department of Chemical Engineering, Northeastern University, Boston, MA, USA.,Neuroscience Department, Albert Einstein College of Medicine, New York, NY, USA
| |
Collapse
|
|
20
|
Chen X, Chen R, Jin R, Huang Z. The role of CXCL chemokine family in the development and progression of gastric cancer. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2020; 13:484-492. [PMID: 32269686 PMCID: PMC7137023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Accepted: 02/06/2020] [Indexed: 06/11/2023]
Abstract
The chemokine (C-X-C motif) ligand (CXCL) family plays an important role in inflammation. In order to understand the role of CXC chemokine family in carcinogenesis, this study explored a group of early gastric cancer (GC) patients, and assessed the level of CXC chemokine ligand (CXCL) in blood samples of patients representing systemic circulation and tumor microenvironment, detected the expression of CXC chemokine receptor (CXCR) in tumor tissues, and measured tumor infiltrating immune cell subsets. 69 patients with GC were included in a single center prospective study and were followed up for 6 years. The level of CXCL1-14 was determined by ELISA and the concentration gradient of chemokine was calculated. Western blot was used to detect the expression of CXCR1, CXCR2, CXCR3, and CXCR4 in tumor tissue. CXCL1-14 expression was inhibited by siRNA in HGC27 cells and then the migration ability of HGC27 cells was detected by cell scratch test. The results of this study showed that the chemokine concentrations of CXCL1, CXCL2, CXCL5, CXCL8, CXCL11, and CXCL13 in peripheral blood and tumor drainage blood of patients without recurrence after treatment were significantly lower than those before treatment. The concentrations of CXCL1, CXCL2, CXCL4, CXCL5, CXCL7, CXCL8, CXCL9, CXCL10, CXCL12, CXCL13, and CXCL14 in peripheral blood and tumor drainage blood were significantly higher than those in patients without recurrence. Patients with low expression of CXCR1 and CXCR3 had lower AFP (alpha fetoprotein), smaller tumor volume, and lower TNM tumor stage. Patients with lower expression of CXCR2 and CXCR4 had higher AFP (alpha fetoprotein) level, larger tumor volume, and higher TNM tumor stage. After down-regulation of CXCLs expression, the migration ability of most cell lines was significantly inhibited. This study suggests that CXCL chemokine family plays an important role in the pathogenesis of GC and can be used as a marker for the development of GC.
Collapse
Affiliation(s)
- Xuyan Chen
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Wenzhou Medical University Zhejiang, P. R. China
| | - Renpin Chen
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Wenzhou Medical University Zhejiang, P. R. China
| | - Ruifang Jin
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Wenzhou Medical University Zhejiang, P. R. China
| | - Zhiming Huang
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Wenzhou Medical University Zhejiang, P. R. China
| |
Collapse
|
|
21
|
Hu B, Tian X, Li Y, Liu Y, Yang T, Han Z, An J, Kong L, Li Y. Epithelial-mesenchymal transition may be involved in the immune evasion of circulating gastric tumor cells via downregulation of ULBP1. Cancer Med 2020; 9:2686-2697. [PMID: 32077634 PMCID: PMC7163085 DOI: 10.1002/cam4.2871] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Revised: 01/08/2020] [Accepted: 01/09/2020] [Indexed: 12/24/2022] Open
Abstract
Background Increasing numbers of studies have demonstrated that circulating tumor cells (CTCs) undergo a phenotypic change termed epithelial‐mesenchymal transition (EMT), and researchers have proposed that EMT might provide CTCs with increased potential to survive in the different microenvironments encountered during metastasis through various ways, such as by increasing cell survival and early colonization. However, the exact role of EMT in CTCs remains unclear. Methods In this study, we identified CTCs of 41 patients with gastric cancer using Cyttel‐CTC and im‐FISH (immune‐fluorescence in situ hybridization) methods, and tested the expression of EMT markers and ULBP1 (a major member of the NKG2D—natural killer [NK] group 2 member D—ligand family) on CTCs. Moreover, we investigated the relationship between the expression of EMT markers and ULBP1 on CTCs and gastric cancer cell lines. Results Our results showed that the CTCs of gastric cancer patients exhibited three EMT marker subtypes, and that the expression of ULBP1 was significantly lower on mesenchymal phenotypic CTCs (M+CTCs) than on epithelial phenotypic CTCs (E+CTCs). EMT induced by TGF‐β in vitro produced a similar phenomenon, and we therefore proposed that EMT might be involved in the immune evasion of CTCs from NK cells by altering the expression of ULBP1. Conclusions Our study indicated that EMT might play a vital role in the immune invasion of CTCs by regulating the expression of ULBP1 on CTCs. These findings could provide potential strategies for targeting the immune evasion capacity of CTCs.
Collapse
Affiliation(s)
- Baoguang Hu
- Department of Gastrointestinal Surgery, Binzhou Medical University Hospital, Binzhou, China
| | - Xiaokun Tian
- Department of Gastrointestinal Surgery, Binzhou Medical University Hospital, Binzhou, China.,Department of Burn and Plastic Surgery, the Sixth People's Hospital of Zibo, Zibo, China
| | - Yanbin Li
- Department of Gastrointestinal Surgery, Binzhou Medical University Hospital, Binzhou, China
| | - Yangchun Liu
- Jiangxi Medical College, Queen Mary College of Nanchang University, Nanchang, China
| | - Tao Yang
- Department of Gastrointestinal Surgery, Binzhou Medical University Hospital, Binzhou, China
| | - Zhaodong Han
- Department of Clinical Laboratory, Binzhou Medical University Hospital, Binzhou, China
| | - Jiajia An
- Department of Clinical Laboratory, Binzhou Medical University Hospital, Binzhou, China
| | - Lingqun Kong
- Department of Hepatobiliary Surgery, Binzhou Medical University Hospital, Binzhou, China
| | - Yuming Li
- Department of Gastrointestinal Surgery, Binzhou Medical University Hospital, Binzhou, China
| |
Collapse
|
|
22
|
Jung JO, Nienhüser H, Schleussner N, Schmidt T. Oligometastatic Gastroesophageal Adenocarcinoma: Molecular Pathophysiology and Current Therapeutic Approach. Int J Mol Sci 2020; 21:E951. [PMID: 32023907 PMCID: PMC7038165 DOI: 10.3390/ijms21030951] [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] [Received: 12/31/2019] [Revised: 01/20/2020] [Accepted: 01/29/2020] [Indexed: 12/15/2022] Open
Abstract
Gastric and esophageal cancers are dreaded malignancies, with a majority of patients presenting in either a locally advanced or metastatic state. Global incidences are rising and the overall prognosis remains poor. The concept of oligometastasis has been established for other tumor entities and is also proposed for upper gastrointestinal tract cancers. This review article explores metastasis mechanisms on the molecular level, specific to esophageal and gastric adenocarcinoma. Existing data and recent studies that deal with upper gastrointestinal tumors in the oligometastatic state are reviewed. Furthermore, current therapeutic targets in gastroesophageal cancers are presented and discussed. Finally, a perspective about future diagnostic and therapeutic strategies is given.
Collapse
Affiliation(s)
| | | | | | - Thomas Schmidt
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany; (J.-O.J.); (H.N.); (N.S.)
| |
Collapse
|
|
23
|
Hu S, Niu J, Zhang R, Li X, Luo M, Sang T, Guo J, Liu J, Ding X, Li X, Ma Y, Gao R. Orexin A associates with inflammation by interacting with OX1R/OX2R receptor and activating prepro-Orexin in cancer tissues of gastric cancer patients. GASTROENTEROLOGIA Y HEPATOLOGIA 2020; 43:240-247. [PMID: 31983458 DOI: 10.1016/j.gastrohep.2019.10.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Revised: 10/05/2019] [Accepted: 10/25/2019] [Indexed: 02/07/2023]
Abstract
OBJECTIVE Gastric cancer (GC) has been become the second leading cause for cancer-associated death. This study aimed to investigate Orexin A levels and associated receptors in tumor tissues of GC patients. PATIENTS AND METHODS Forty-six consecutive gastric cancer patients (GC, n=46) and 13 chronic atrophic gastritis patients (CAG, n=13) were recruited. Meanwhile, 18 health individuals visiting Medical Examination Department were involved as control (N group, n=18). ELISA was used to examine Orexin A concentration. Immunohistochemistry assay was used to examine OX1R and OX2R. HE staining was applied to evaluate inflammation. qRT-PCR was employed to detect OX1R, OX2R, prepro-Orexin mRNAs. Serum Helicobacter pylori (H. pylori) infection was measured. RESULTS Orexin A expression in GC patients was significantly up-regulated compared to N group and CAG group (p<0.05). Orexin A expression was increased in CAG group compared to N group (p<0.05). Gastric cancer tissues exhibited significantly obvious inflammation compared to N group and CAG group (p<0.05). OX1R and OX2R expressions were significantly down-regulated in GC group compared to N group and CAG group (p<0.05). OX1R and OX2R were lower significantly in GC group compared to CAG group (p<0.05). Prepro-Orexin was significantly depleted in tumor tissues of GC group compared to N group and CAG group (p<0.05). Orexin A expression was un-associated with gender, age and differential grades (p>0.05). CAG and GC patients demonstrated higher H. pylori infection rates. CONCLUSION Orexin A was associated with inflammation by interacting with OX1R/OX2R receptor and activating prepro-Orexin in tumor tissues of gastric cancer patients.
Collapse
Affiliation(s)
- Shengjuan Hu
- Digestive division, Endoscopic center, People's Hospital of Ningxia Hui Autunomous Region, Yinchuan, China.
| | - Jianguo Niu
- Ningxia Key Laboratory of Cerebrocranial Diseases, Ningxia Medical University, Yinchuan, China
| | - Rong Zhang
- 521 Hospital of Norinco Group, Xi'an, China
| | - Ximei Li
- Digestive division, Endoscopic center, People's Hospital of Ningxia Hui Autunomous Region, Yinchuan, China
| | - Ming Luo
- Digestive division, Endoscopic center, People's Hospital of Ningxia Hui Autunomous Region, Yinchuan, China
| | - Tian Sang
- Digestive division, Endoscopic center, People's Hospital of Ningxia Hui Autunomous Region, Yinchuan, China
| | - Jianyang Guo
- Digestive division, Endoscopic center, People's Hospital of Ningxia Hui Autunomous Region, Yinchuan, China
| | - Jun Liu
- Digestive division, Endoscopic center, People's Hospital of Ningxia Hui Autunomous Region, Yinchuan, China
| | - Xiaoling Ding
- Digestive division, Endoscopic center, People's Hospital of Ningxia Hui Autunomous Region, Yinchuan, China
| | - Xuemei Li
- Digestive division, Endoscopic center, People's Hospital of Ningxia Hui Autunomous Region, Yinchuan, China
| | - Yuhong Ma
- Digestive division, Endoscopic center, People's Hospital of Ningxia Hui Autunomous Region, Yinchuan, China
| | - Ruiping Gao
- Digestive division, Endoscopic center, People's Hospital of Ningxia Hui Autunomous Region, Yinchuan, China
| |
Collapse
|
|
24
|
Cui F, Tang H, Tan J, Hu J. Spindle pole body component 25 regulates stemness of prostate cancer cells. Aging (Albany NY) 2019; 10:3273-3282. [PMID: 30408771 PMCID: PMC6286856 DOI: 10.18632/aging.101631] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Accepted: 10/28/2018] [Indexed: 12/19/2022]
Abstract
Spindle pole body component 25 (SPC25) is a component of NDC80 complex that controls spindle assembly checkpoint in the microtubule-binding domain of kinetochores. We recently showed that SPC25 is required for prostate cancer (PrC) cell proliferation and cell cycle progression, and here we investigated whether SPC25 may be a Cancer stem cell (CSC) marker in PrC. We found that the levels of SPC25 were higher in PrC samples than paired normal prostate tissue. The overall survival of PrC patients with high SPC25 was poorer than those with low SPC25. PrC cell lines were transduced with two vectors carrying a luciferase reporter and a mCherry fluorescent reporter under a cytomegalovirus promoter and a nuclear green fluorescent protein reporter under the control of a SPC25 promoter, respectively, to allow differentiating SPC25+ from SPC25- PrC cells by flow cytometry. Compared to SPC25- cells, SPC25+ cells formed significantly more tumor spheres in culture, appeared to be more resistant towards docetaxel-induced cell apoptosis, and generated larger tumors with higher frequency after serial adoptive transplantation. Thus, our data suggest that SPC25 may be highly expressed in the CSC-like cells in PrC and could be a promising target for effective treatment of PrC.
Collapse
Affiliation(s)
- Feilun Cui
- Department of Urology, Zhenjiang First People's Hospital, Zhenjiang 212002, China
| | - Huaming Tang
- Department of Urology, Zhenjiang First People's Hospital, Zhenjiang 212002, China
| | - Jian Tan
- Department of Urology, Zhenjiang First People's Hospital, Zhenjiang 212002, China
| | - Jianpeng Hu
- Department of Urology, Zhenjiang First People's Hospital, Zhenjiang 212002, China
| |
Collapse
|
|
25
|
Jin KT, Chen XY, Lan HR, Wang SB, Ying XJ, Abdi SM, Wang W, Hu ZM, Mou XZ. Current progress in the clinical use of circulating tumor cells as prognostic biomarkers. Cancer Cytopathol 2019; 127:739-749. [PMID: 31589381 DOI: 10.1002/cncy.22189] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2019] [Revised: 09/05/2019] [Accepted: 09/06/2019] [Indexed: 12/11/2022]
Abstract
The process of metastasis is characterized by the shedding of tumor cells into the bloodstream, where they are transported to other parts of the body to seed new tumors. These cells, known as circulating tumor cells (CTCs), have the potential to reveal much about an individual cancer case, and theoretically can aid in the prediction of outcomes and design of precision treatments. Recent advances in technology now allow for the robust and reproducible characterization of CTCs from a simple blood draw. Both the number of circulating cells and important molecular characteristics correlated with clinical phenotypes such as drug resistance can be obtained and used for real-time prognostic analysis. Molecular characterization can provide a snapshot of the activity of the main tumor (serving as a "liquid biopsy") and early warnings concerning changes such as the development of resistance, and aid in predicting the efficacy of different therapeutic approaches for treatment optimization. Herein, the authors review the current clinical use of CTCs as prognostic biomarkers for several different cancers. The quantification of CTCs can lead to more accurate staging and decision making regarding options such as adjuvant chemotherapy.
Collapse
Affiliation(s)
- Ke-Tao Jin
- Department of Colorectal Surgery, Shaoxing People's Hospital, Zhejiang University School of Medicine, Shaoxing, China
| | - Xiao-Yi Chen
- Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China.,Clinical Research Institute, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China
| | - Huan-Rong Lan
- Department of Breast and Thyroid Surgery, Shaoxing People's Hospital, Zhejiang University School of Medicine, Shaoxing, China
| | - Shi-Bing Wang
- Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China.,Clinical Research Institute, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China
| | - Xiao-Jiang Ying
- Department of Colorectal Surgery, Shaoxing People's Hospital, Zhejiang University School of Medicine, Shaoxing, China
| | - Siyad Mohamed Abdi
- Department of Colorectal Surgery, Shaoxing People's Hospital, Zhejiang University School of Medicine, Shaoxing, China
| | - Wei Wang
- Department of Colorectal Surgery, Shaoxing People's Hospital, Zhejiang University School of Medicine, Shaoxing, China
| | - Zhi-Ming Hu
- Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China.,Department of Hepatobiliary and Pancreatic Surgery, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China
| | - Xiao-Zhou Mou
- Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China.,Clinical Research Institute, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China
| |
Collapse
|
|
26
|
Yuan Y, Yangmei Z, Rongrong S, Xiaowu L, Youwei Z, Sun S. Sotrastaurin attenuates the stemness of gastric cancer cells by targeting PKCδ. Biomed Pharmacother 2019; 117:109165. [PMID: 31261030 DOI: 10.1016/j.biopha.2019.109165] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2019] [Revised: 06/18/2019] [Accepted: 06/20/2019] [Indexed: 12/24/2022] Open
Abstract
Gastric cancer (GC) is one of the most lethal malignancies. Chemoresistance and metastasis are the main cause of treatment failure. Cancer stem cells (CSCs) have been proven to be essential for cancer metastasis and chemoresistance. PKCδ (protein kinase C-δ), a novel member of PKC family, has been validated as a synthetic lethal target in multiple cancers, and contributes to tyrosine kinase inhibitors (TKI) resistance in EGFR-mutant NSCLC (non-small cell lung cancer) patients. However, its role in GC is unclear. Here, we systematically investigate its role in GC, especially in regulating GC stem cell-like properties. We found that PKCδ positively regulated the metastasis, chemoresistance, and stem cell-like characteristics of GC cells, and its inhibitor sotrastaurin could rescue the above effects mediated by PKCδ. Importantly, sotrastaurin could also weaken metastasis, chemoresistance, and stem cell-like characteristics of adriamycin-resistant GC cells via PKCδ suppression, indicating sotrastaurin is an ideal candidate for combinational therapy to overcome chemoresistance for GC.
Collapse
Affiliation(s)
- Yuan Yuan
- Department of Medical Oncology, Xuzhou Central Hospital, Xuzhou Medical University, XuZhou, 221009, China
| | - Zhang Yangmei
- Department of Medical Oncology, Xuzhou Central Hospital, Xuzhou Medical University, XuZhou, 221009, China
| | - Sun Rongrong
- Department of Medical Oncology, Xuzhou Central Hospital, Xuzhou Medical University, XuZhou, 221009, China
| | - Li Xiaowu
- Department of Medical Oncology, Xuzhou Central Hospital, Xuzhou Medical University, XuZhou, 221009, China
| | - Zhang Youwei
- Department of Medical Oncology, Xuzhou Central Hospital, Xuzhou Medical University, XuZhou, 221009, China.
| | - Sanyuan Sun
- Department of Medical Oncology, Xuzhou Central Hospital, Xuzhou Medical University, XuZhou, 221009, China.
| |
Collapse
|
|
27
|
Limited Sensitivity of Circulating Tumor DNA Detection by Droplet Digital PCR in Non-Metastatic Operable Gastric Cancer Patients. Cancers (Basel) 2019; 11:cancers11030396. [PMID: 30901876 PMCID: PMC6468548 DOI: 10.3390/cancers11030396] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Revised: 03/14/2019] [Accepted: 03/18/2019] [Indexed: 02/07/2023] Open
Abstract
This study was designed to monitor circulating tumor DNA (ctDNA) levels during perioperative chemotherapy in patients with non-metastatic gastric adenocarcinoma. Plasma samples were prospectively collected in patients undergoing perioperative chemotherapy for non-metastatic gastric adenocarcinoma (excluding T1N0) prior to the initiation of perioperative chemotherapy, before and after surgery (NCT02220556). In each patient, mutations retrieved by targeted next-generation sequencing (NGS) on tumor samples were then tracked in circulating cell-free DNA from 4 mL of plasma by droplet digital PCR. Thirty-two patients with a diagnosis of non-metastatic gastric adenocarcinoma were included. A trackable mutation was identified in the tumor in 20 patients, seven of whom experienced relapse during follow-up. ctDNA was detectable in four patients (N = 4/19, sensitivity: 21%; 95% confidence interval CI = 8.5–43%, no baseline plasma sample was available for one patient), with a median allelic frequency (MAF) of 1.6% (range: 0.8–2.3%). No patient with available plasma samples (N = 0/18) had detectable ctDNA levels before surgery. After surgery, one of the 13 patients with available plasma samples had a detectable ctDNA level with a low allelic frequency (0.7%); this patient experienced a very short-term distant relapse only 3 months after surgery. No ctDNA was detected after surgery in the other four patients with available plasma samples who experienced a later relapse (median = 14.4, range: 9.3–26 months). ctDNA monitoring during preoperative chemotherapy and after surgery does not appear to be a useful tool in clinical practice for non-metastatic gastric cancer to predict the efficacy of chemotherapy and subsequent relapse, essentially due to the poor sensitivity of ctDNA detection.
Collapse
|
|
28
|
Abalde-Cela S, Piairo P, Diéguez L. The Significance of Circulating Tumour Cells in the Clinic. Acta Cytol 2019; 63:466-478. [PMID: 30820013 DOI: 10.1159/000495417] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2018] [Accepted: 11/08/2018] [Indexed: 12/16/2022]
Abstract
BACKGROUND Despite the hype about circulating tumour cells (CTCs) in the early 2000s and their potential in the diagnosis of metastasis, in recent years, the hope for personalised cancer management relies more on circulating tumour (ct)DNA that has entered the clinic in a much more efficient way. So far, approved methods for CTCs in the clinic only provide the counting of CTCs, which enables monitoring of the progression of metastatic breast, prostate, and colorectal cancer patients with therapy. Approved methods for ctDNA facilitate the analysis of specific mutations in lung cancer, thereby providing indications for potentially successful treatments. This situation inclined the balance towards molecular analysis in liquid biopsy, leveraged by new technologies and companies providing broader mutation and gene expression analysis towards the early diagnosis of cancer. STUDY DESIGN We conducted a search for the studies published to date that provide details about the significance of CTCs in the clinic. RESULTS Many studies and clinical trials have demonstrated the potential of CTCs in patient screening, early diagnosis, therapy resistance, and patient prognosis. CONCLUSIONS Large multi-centre studies are still needed to formally validate the clinical relevance of CTCs. Meticulous design of the clinical trials is a crucial point to achieve this long-sought objective.
Collapse
Affiliation(s)
- Sara Abalde-Cela
- Medical Devices Research Group, Department of Life Sciences, INL - International Iberian Nanotechnology Laboratory, Braga, Portugal
| | - Paulina Piairo
- Medical Devices Research Group, Department of Life Sciences, INL - International Iberian Nanotechnology Laboratory, Braga, Portugal
- iMM- Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, Lisboa, Portugal
| | - Lorena Diéguez
- Medical Devices Research Group, Department of Life Sciences, INL - International Iberian Nanotechnology Laboratory, Braga, Portugal,
| |
Collapse
|
|
29
|
Wang L, Liu Z, Kou H, He H, Zheng B, Zhou L, Yang Y. Double Contrast-Enhanced Ultrasonography in Preoperative T Staging of Gastric Cancer: A Comparison With Endoscopic Ultrasonography. Front Oncol 2019; 9:66. [PMID: 30809510 PMCID: PMC6380108 DOI: 10.3389/fonc.2019.00066] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Accepted: 01/24/2019] [Indexed: 12/15/2022] Open
Abstract
Objective: To compare the precision of double contrast-enhanced ultrasonography (DCEUS) to endoscopic ultrasonography (EUS) in preoperative T staging of gastric cancers. Methods: This retrospective study consisted of 158 pathologically confirmed gastric cancer patients. All patients underwent DCEUS (intravenous contrast-enhanced ultrasonography combined with oral contrast-enhanced ultrasonography) and endoscopic ultrasonography (EUS) preoperatively. The histopathological findings of resected specimens were compared with the results of DCEUS and EUS retrospectively. Results: The accuracy of DCEUS and EUS in evaluating the T staging of gastric cancer were 82.3% (T1 62.5%,T2 84.4%,T3 87.9%,T4 91.3%) and 76.6% (T1 84.4%,T2 82.2%,T3 72.4%,T4 65.2%), respectively. There were no significant differences between the methods for the overall T staging accuracy (χ2 = 1.569, P = 0.210). But EUS was superior to DCEUS for T1 stage (χ2 = 3.925, P = 0.048) and DCEUS was superior to EUS for T3 stage (χ2 = 4.393, P = 0.036) and T4 stage (χ2 = 4.600, P = 0.032). Conclusion: DCEUS is a convenient and noninvasive method with high precision, which can be used as the primary imaging technique for advanced gastric cancer T staging. In early gastric cancer, we should prefer EUS. Two methods are complementary for assessing tumor invasion depth of gastric cancer.
Collapse
Affiliation(s)
- Liang Wang
- Department of Ultrasound, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Zhe Liu
- Department of Ultrasound, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.,Wenzhou Institute of Biomaterials and Engineering, Chinese Academy of Sciences, Wenzhou, China
| | - Hongju Kou
- Department of Ultrasound, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Huiliao He
- Wenzhou Institute of Biomaterials and Engineering, Chinese Academy of Sciences, Wenzhou, China
| | - Bo Zheng
- Department of Gastroenterology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Lingling Zhou
- Department of Pathology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yan Yang
- Department of Ultrasound, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| |
Collapse
|
|
30
|
Koldby KM, Mortensen MB, Detlefsen S, Pfeiffer P, Thomassen M, Kruse TA. Tumor-specific genetic aberrations in cell-free DNA of gastroesophageal cancer patients. J Gastroenterol 2019; 54:108-121. [PMID: 30242476 DOI: 10.1007/s00535-018-1508-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2018] [Accepted: 09/04/2018] [Indexed: 02/04/2023]
Abstract
The applicability of liquid biopsies is studied intensively in all types of cancer and analysis of circulating tumor DNA (ctDNA) has recently been implemented clinically for mutation detection in lung cancer. ctDNA may provide information about tumor quantity and mutations present in the tumor, and as such have many potential applications in diagnosis and treatment of cancer. It has been suggested that ctDNA analysis may overcome the issue of intra-tumor heterogeneity faced by tissue biopsies and serve as an additional diagnostic tool. Furthermore, liquid biopsies are potentially helpful for monitoring of treatment response as well as detection of minimal residual disease and relapse. Gastroesophageal cancers (GEC) have high mortality rates and the majority of patients present with advanced stage at diagnosis or succumb due to disease recurrence even after radical resection of the primary tumor. Biomarkers that can help optimize treatment strategy are thus highly desirable. The present study is a review of published data on ctDNA in GEC patients. We identified 25 studies in which tumor-specific genetic aberrations were investigated in plasma or serum and discuss these in relation to the methods applied for ctDNA analysis. The methods used for ctDNA detection greatly influence the sensitivity of the analysis and, therefore, the potential clinical applications. We found that studies of ctDNA in GEC, although limited in number, are promising for several applications such as genetic profiling of tumors and monitoring of disease progression. However, more studies are needed to establish if and how this analysis can be clinically implemented.
Collapse
Affiliation(s)
- Kristina Magaard Koldby
- Department of Clinical Genetics, Odense University Hospital, J.B. Winsløws Vej 4, Odense, Denmark. .,Human Genetics, Department of Clinical Research, University of Southern Denmark, Sdr. Boulevard 29, Odense, Denmark.
| | - Michael Bau Mortensen
- Department of Surgery, Odense University Hospital, J.B. Winsløws Vej 4, Odense, Denmark
| | - Sönke Detlefsen
- Department of Pathology, Odense University Hospital, J.B. Winsløws Vej 15, Odense, Denmark
| | - Per Pfeiffer
- Department of Oncology, Odense University Hospital, J.B. Winsløws Vej 4, Odense, Denmark
| | - Mads Thomassen
- Department of Clinical Genetics, Odense University Hospital, J.B. Winsløws Vej 4, Odense, Denmark.,Human Genetics, Department of Clinical Research, University of Southern Denmark, Sdr. Boulevard 29, Odense, Denmark
| | - Torben A Kruse
- Department of Clinical Genetics, Odense University Hospital, J.B. Winsløws Vej 4, Odense, Denmark.,Human Genetics, Department of Clinical Research, University of Southern Denmark, Sdr. Boulevard 29, Odense, Denmark
| |
Collapse
|
|
31
|
You X, Wang Y, Wu J, Liu Q, Chen D, Tang D, Wang D. Aberrant Cytokeratin 20 mRNA Expression in Peripheral Blood and Lymph Nodes Indicates Micrometastasis and Poor Prognosis in Patients With Gastric Carcinoma. Technol Cancer Res Treat 2019; 18:1533033819832856. [PMID: 30827194 PMCID: PMC6856971 DOI: 10.1177/1533033819832856] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Several studies suggest that peripheral blood and lymph node micrometastases may be a causative factor for gastric cancer recurrence. Cytokeratin 20 shows enriched expression in intestinal epithelial cells. This study aimed to evaluate the clinical utility of monitoring cytokeratin 20 levels in peripheral blood and lymph nodes of patients with gastric cancer for detecting micrometastasis and predicting prognosis. We detected messenger RNA levels of cytokeratin 20 in gastric cancer cell lines and in the peripheral blood of 125 patients (85 patients with gastric cancer and 40 patients with benign neoplasm) by fluorescence quantitative real-time polymerase chain reaction both before and after radical resection. In all, 1586 lymph node samples from 85 patients with gastric cancer were evaluated for cytokeratin 20 expression using real-time polymerase chain reaction, as well as by immunohistochemistry staining with anti-pan-keratin and anti-cytokeratin 20 antibodies. All patients underwent follow-up until cancer-related death or for more than 3 years after tumor resection. We found that elevated cytokeratin 20 expression in peripheral blood as detected by quantitative real-time polymerase chain reaction closely correlates with poor clinicopathological characteristics. Detecting cytokeratin 20 messenger RNA in the lymph nodes by quantitative real-time polymerase chain reaction enabled more accurate determination of the clinicopathological staging of gastric cancer, best treatment approach, and prognosis. Our findings show that patients with increased cytokeratin 20 messenger RNA expression in the peripheral blood or lymph nodes have a shorter time to recurrence and poorer overall survival.
Collapse
Affiliation(s)
- Xiaolan You
- Department of Gastrointestinal Surgery, The Hospital Affiliated to Medical
School of Yangzhou University (Taizhou People's Hospital), Taizhou, Jiangsu Province,
China
- Xiaolan You, PhD, Department of Gastrointestinal
Surgery, The Hospital Affiliated to Medical School of Yangzhou University (Taizhou
People's Hospital), No 8 South Dongfeng Road, Taizhou 225300, Jiangsu Province, China.
| | - Yuanjie Wang
- Department of Gastrointestinal Surgery, The Hospital Affiliated to Medical
School of Yangzhou University (Taizhou People's Hospital), Taizhou, Jiangsu Province,
China
| | - Jian Wu
- Department of Gastrointestinal Surgery, The Hospital Affiliated to Medical
School of Yangzhou University (Taizhou People's Hospital), Taizhou, Jiangsu Province,
China
| | - Qinghong Liu
- Department of Gastrointestinal Surgery, The Hospital Affiliated to Medical
School of Yangzhou University (Taizhou People's Hospital), Taizhou, Jiangsu Province,
China
| | - Dehu Chen
- Department of Gastrointestinal Surgery, The Hospital Affiliated to Medical
School of Yangzhou University (Taizhou People's Hospital), Taizhou, Jiangsu Province,
China
| | - Dong Tang
- Department of Gastrointestinal Surgery, Clinical Medical College of Yangzhou
University, Subei People’s Hospital of Jiangsu Province, Yangzhou Jiangsu Province,
China
| | - Daorong Wang
- Department of Gastrointestinal Surgery, Clinical Medical College of Yangzhou
University, Subei People’s Hospital of Jiangsu Province, Yangzhou Jiangsu Province,
China
| |
Collapse
|
|
32
|
Saini A, Pershad Y, Albadawi H, Kuo M, Alzubaidi S, Naidu S, Knuttinen MG, Oklu R. Liquid Biopsy in Gastrointestinal Cancers. Diagnostics (Basel) 2018; 8:diagnostics8040075. [PMID: 30380690 PMCID: PMC6316210 DOI: 10.3390/diagnostics8040075] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Revised: 10/24/2018] [Accepted: 10/24/2018] [Indexed: 12/18/2022] Open
Abstract
Liquid biopsy is the sampling of any biological fluid in an effort to enrich and analyze a tumor's genetic material. Peripheral blood remains the most studied liquid biopsy material, with circulating tumor cells (CTC's) and circulating tumor DNA (ctDNA) allowing the examination and longitudinal monitoring of a tumors genetic landscape. With applications in cancer screening, prognostic stratification, therapy selection and disease surveillance, liquid biopsy represents an exciting new paradigm in the field of cancer diagnostics and offers a less invasive and more comprehensive alternative to conventional tissue biopsy. Here, we examine liquid biopsies in gastrointestinal cancers, specifically colorectal, gastric, and pancreatic cancers, with an emphasis on applications in diagnostics, prognostics and therapeutics.
Collapse
Affiliation(s)
- Aman Saini
- Division of Vascular and Interventional Radiology, Laboratory for Minimally Invasive Therapeutics, Mayo Clinic, Phoenix, AZ 85054, USA.
| | - Yash Pershad
- Division of Vascular and Interventional Radiology, Laboratory for Minimally Invasive Therapeutics, Mayo Clinic, Phoenix, AZ 85054, USA.
| | - Hassan Albadawi
- Division of Vascular and Interventional Radiology, Laboratory for Minimally Invasive Therapeutics, Mayo Clinic, Phoenix, AZ 85054, USA.
| | - Malia Kuo
- Division of Vascular and Interventional Radiology, Laboratory for Minimally Invasive Therapeutics, Mayo Clinic, Phoenix, AZ 85054, USA.
| | - Sadeer Alzubaidi
- Division of Vascular and Interventional Radiology, Laboratory for Minimally Invasive Therapeutics, Mayo Clinic, Phoenix, AZ 85054, USA.
| | - Sailendra Naidu
- Division of Vascular and Interventional Radiology, Laboratory for Minimally Invasive Therapeutics, Mayo Clinic, Phoenix, AZ 85054, USA.
| | - M-Grace Knuttinen
- Division of Vascular and Interventional Radiology, Laboratory for Minimally Invasive Therapeutics, Mayo Clinic, Phoenix, AZ 85054, USA.
| | - Rahmi Oklu
- Division of Vascular and Interventional Radiology, Laboratory for Minimally Invasive Therapeutics, Mayo Clinic, Phoenix, AZ 85054, USA.
| |
Collapse
|
|
33
|
Yang C, Zhang N, Wang S, Shi D, Zhang C, Liu K, Xiong B. Wedge-shaped microfluidic chip for circulating tumor cells isolation and its clinical significance in gastric cancer. J Transl Med 2018; 16:139. [PMID: 29792200 PMCID: PMC5966930 DOI: 10.1186/s12967-018-1521-8] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2018] [Accepted: 05/16/2018] [Indexed: 12/11/2022] Open
Abstract
Background Circulating tumor cells (CTCs) have great potential in both basic research and clinical application for the managements of cancer. However, the complicated fabrication processes and expensive materials of the existing CTCs isolation devices, to a large extent, limit their clinical translation and CTCs’ clinical value. Therefore, it remains to be urgently needed to develop a new platform for achieving CTCs detection with low-cost, mass-producible but high performance. Methods In the present study, we introduced a novel wedge-shaped microfluidic chip (named CTC-ΔChip) fabricated by two pieces of glass through wet etching and thermal bonding technique for CTCs isolation, which achieved CTCs enrichment by different size without cell surface expression markers and CTCs identification with three-color immunocytochemistry method (CK+/CD45−/Nucleus+). We validated the feasibility of CTC-ΔChip for detecting CTCs from different types of solid tumor. Furthermore, we applied the newly-developed platform to investigate the clinical significance of CTCs in gastric cancer (GC). Results Based on “label-free” characteristic, the capture efficiency of CTC-ΔChip can be as high as 93.7 ± 3.2% in DMEM and 91.0 ± 3.0% in whole blood sample under optimized conditions. Clinically, CTC-ΔChip exhibited the feasibility of detecting CTCs from different types of solid tumor, and it identified 7.30 ± 7.29 CTCs from 2 mL peripheral blood with a positive rate of 75% (30/40) in GC patients. Interestingly, we found that GC CTCs count was significantly correlated with multiple systemic inflammation indexes, including the lymphocyte count, platelet count, the level of neutrophil to lymphocyte ratio and platelet to lymphocyte ratio. In addition, we also found that both the positivity rate and CTCs count were significantly associated with multiple clinicopathology parameters. Conclusions Our novel CTC-ΔChip shows high performance for detecting CTCs from less volume of blood samples of cancer patients and important clinical significance in GC. Owing to the advantages of low-cost and mass-producible, CTC-ΔChip holds great potential of clinical application for cancer therapeutic guidance and prognostic monitoring in the future. Electronic supplementary material The online version of this article (10.1186/s12967-018-1521-8) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Chaogang Yang
- Department of Gastrointestinal Surgery & Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China.,Hubei Key Laboratory of Tumor Biological Behaviors, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China.,Hubei Cancer Clinical Study Center, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China
| | - Nangang Zhang
- College of Electronic and Electrical Engineering, Wuhan Textile University, No.1 Sunshine Avenue, Hongshan District, Wuhan, 430200, China
| | - Shuyi Wang
- Department of Gastrointestinal Surgery & Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China.,Hubei Key Laboratory of Tumor Biological Behaviors, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China.,Hubei Cancer Clinical Study Center, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China
| | - Dongdong Shi
- Department of Gastrointestinal Surgery & Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China.,Hubei Key Laboratory of Tumor Biological Behaviors, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China.,Hubei Cancer Clinical Study Center, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China
| | - Chunxiao Zhang
- Department of Gastrointestinal Surgery & Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China.,Hubei Key Laboratory of Tumor Biological Behaviors, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China.,Hubei Cancer Clinical Study Center, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China
| | - Kan Liu
- College of Electronic and Electrical Engineering, Wuhan Textile University, No.1 Sunshine Avenue, Hongshan District, Wuhan, 430200, China. .,School of Life Science and Technology, University of Electronic Science and Technology of China, No.4, Section 2, North Jianshe Road, Chengdu, 610054, China.
| | - Bin Xiong
- Department of Gastrointestinal Surgery & Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China. .,Hubei Key Laboratory of Tumor Biological Behaviors, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China. .,Hubei Cancer Clinical Study Center, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China.
| |
Collapse
|
|
34
|
Li G, Su Q, Liu H, Wang D, Zhang W, Lu Z, Chen Y, Huang X, Li W, Zhang C, He Y, Fu L, Bi J. Frizzled7 Promotes Epithelial-to-mesenchymal Transition and Stemness Via Activating Canonical Wnt/β-catenin Pathway in Gastric Cancer. Int J Biol Sci 2018; 14:280-293. [PMID: 29559846 PMCID: PMC5859474 DOI: 10.7150/ijbs.23756] [Citation(s) in RCA: 79] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2017] [Accepted: 01/06/2018] [Indexed: 12/25/2022] Open
Abstract
Aberrant activation of Wnt signaling is a crucial event in tumor development and metastasis. Wnt signaling is commonly divided into canonical and non-canonical signaling pathways based on whether β-catenin is activated (canonical). The two signaling pathways are initiated by Wnt ligand binding to the surface Frizzled (FZD) receptors, and regulate cancer stem cell self-renewal and epithelial-mesenchymal transition (EMT). Frizzled 7 (FZD7), a member of Frizzled family, promotes cell proliferation and invasiveness in many cancers, suggesting that FZD7 transmitting Wnt signaling is important for driving cancer growth. FZD7 expression has been reported to be up-regulated in human primary gastric cancer tissues. However, the molecular mechanism by which FZD7 promotes gastric cancer(GC) development and progression is not fully understood. Our present study showed that FZD7 was overexpressed in clinical GC samples, and thus was correlated with tumor invasion, lymphatic and organ metastasis, late TNM stages and poor patient survival. The endogenous expression of FZD7 was significantly increased in cancer stem cell-enriched spheres compared with adherent cells. Furthermore, RNA interference-mediated silencing of FZD7 inhibited proliferation, migration and invasion in gastric cancer cells. Moreover, ablation of FZD7 down-regulated EMT and the expression levels of cancer stem cell markers, and these inhibitions were associated with attenuated canonical Wnt/β-catenin signaling. The results suggest that Wnt canonical pathway may contribute to tumorigenesis and metastasis, indicating that FZD7 could be a potential therapeutic target for gastric cancer.
Collapse
Affiliation(s)
- Guanman Li
- Laboratory of General Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, Guangdong, China
| | - Qiao Su
- Animal Center, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, Guangdong, China
| | - Haibo Liu
- Key Laboratory for Major Obstetric Diseases of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou 510000, Guangdong, China
| | - Dong Wang
- Department of Clinical Laboratory, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, Guangdong, China
| | - Wenhui Zhang
- Department of Pathology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, Guangdong, China
| | - Zhenhai Lu
- Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Guangzhou 510060, Guangdong, China
| | - Yu Chen
- Department of Immunity, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, Guangdong, China
| | - Xiaohui Huang
- Laboratory of General Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, Guangdong, China
| | - Wen Li
- Laboratory of General Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, Guangdong, China
| | - Changhua Zhang
- Gastrointestinal Surgery Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, Guangdong, China
| | - Yulong He
- Gastrointestinal Surgery Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, Guangdong, China
| | - Li Fu
- Guangdong Key Laboratory for Genome Stability & Disease Prevention, Department of Pharmacology and Cancer Research Centre, School of Medicine, Shenzhen University, Shenzhen, China
| | - Jiong Bi
- Laboratory of General Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, Guangdong, China
| |
Collapse
|
|
35
|
Nordgård O, Tjensvoll K, Gilje B, Søreide K. Circulating tumour cells and DNA as liquid biopsies in gastrointestinal cancer. Br J Surg 2018; 105:e110-e120. [DOI: 10.1002/bjs.10782] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2017] [Revised: 10/02/2017] [Accepted: 11/09/2017] [Indexed: 12/15/2022]
Abstract
Abstract
Background
Blood is the most extensively studied body fluid and, because it contains circulating tumour cells (CTCs) and circulating tumour-derived cell-free DNA (ctDNA), it may represent a liquid biopsy for cancer. Methods for enrichment and detection of CTCs and ctDNA, their clinical applications and future opportunities in gastrointestinal cancers were the focus of this review.
Methods
The PubMed database was searched for literature up to 24 June 2017, with a focus on the past 10 years. Identified articles were further scrutinized for relevant references. Articles were those in English relating to colorectal, gastric and pancreatic cancer.
Results
Both CTCs and ctDNA are in low abundance compared with other cellular components of blood, but effective enrichment and highly sensitive techniques are available for their detection. Potential clinical applications of these liquid biopsies include screening, prognostic stratification, therapy administration, monitoring of treatment effect or resistance, and surveillance. Liquid biopsies provide opportunities to reduce the need for invasive tissue sampling, especially in the context of intratumoral heterogeneity and the need for tumour genotyping.
Conclusion
Liquid biopsies have applications in gastrointestinal cancers to improve clinical decision-making.
Collapse
Affiliation(s)
- O Nordgård
- Department of Haematology and Oncology, Stavanger University Hospital, Stavanger, Norway
- Department of Mathematics and Natural Science, University of Stavanger, Stavanger, Norway
| | - K Tjensvoll
- Department of Haematology and Oncology, Stavanger University Hospital, Stavanger, Norway
| | - B Gilje
- Department of Haematology and Oncology, Stavanger University Hospital, Stavanger, Norway
| | - K Søreide
- Department of Gastrointestinal Surgery, Stavanger University Hospital, Stavanger, Norway
- Department of Clinical Medicine, University of Bergen, Bergen, Norway
- Clinical Surgery, Royal Infirmary of Edinburgh and University of Edinburgh, Edinburgh, UK
| |
Collapse
|
|
36
|
Huang Q, Wang Y, Chen X, Wang Y, Li Z, Du S, Wang L, Chen S. Nanotechnology-Based Strategies for Early Cancer Diagnosis Using Circulating Tumor Cells as a Liquid Biopsy. Nanotheranostics 2018; 2:21-41. [PMID: 29291161 PMCID: PMC5743836 DOI: 10.7150/ntno.22091] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2017] [Accepted: 10/10/2017] [Indexed: 12/11/2022] Open
Abstract
Circulating tumor cells (CTCs) are cancer cells that shed from a primary tumor and circulate in the bloodstream. As a form of “tumor liquid biopsy”, CTCs provide important information for the mechanistic investigation of cancer metastasis and the measurement of tumor genotype evolution during treatment and disease progression. However, the extremely low abundance of CTCs in the peripheral blood and the heterogeneity of CTCs make their isolation and characterization major technological challenges. Recently, nanotechnologies have been developed for sensitive CTC detection; such technologies will enable better cell and molecular characterization and open up a wide range of clinical applications, including early disease detection and evaluation of treatment response and disease progression. In this review, we summarize the nanotechnology-based strategies for CTC isolation, including representative nanomaterials (such as magnetic nanoparticles, gold nanoparticles, silicon nanopillars, nanowires, nanopillars, carbon nanotubes, dendrimers, quantum dots, and graphene oxide) and microfluidic chip technologies that incorporate nanoroughened surfaces and discuss their key challenges and perspectives in CTC downstream analyses, such as protein expression and genetic mutations that may reflect tumor aggressiveness and patient outcome.
Collapse
Affiliation(s)
- Qinqin Huang
- Key Laboratory of Combinatorial Biosynthesis and Drug Discovery of Ministry of Education, School of Pharmaceutical Sciences, and Brain Center, Zhongnan Hospital, and Medical Research Institute, Wuhan University, Wuhan 430072, China
| | - Yin Wang
- Key Laboratory of Combinatorial Biosynthesis and Drug Discovery of Ministry of Education, School of Pharmaceutical Sciences, and Brain Center, Zhongnan Hospital, and Medical Research Institute, Wuhan University, Wuhan 430072, China
| | - Xingxiang Chen
- Key Laboratory of Combinatorial Biosynthesis and Drug Discovery of Ministry of Education, School of Pharmaceutical Sciences, and Brain Center, Zhongnan Hospital, and Medical Research Institute, Wuhan University, Wuhan 430072, China
| | - Yimeng Wang
- Key Laboratory of Combinatorial Biosynthesis and Drug Discovery of Ministry of Education, School of Pharmaceutical Sciences, and Brain Center, Zhongnan Hospital, and Medical Research Institute, Wuhan University, Wuhan 430072, China
| | - Zhiqiang Li
- Key Laboratory of Combinatorial Biosynthesis and Drug Discovery of Ministry of Education, School of Pharmaceutical Sciences, and Brain Center, Zhongnan Hospital, and Medical Research Institute, Wuhan University, Wuhan 430072, China
| | - Shiming Du
- Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, 442000, China
| | - Lianrong Wang
- Key Laboratory of Combinatorial Biosynthesis and Drug Discovery of Ministry of Education, School of Pharmaceutical Sciences, and Brain Center, Zhongnan Hospital, and Medical Research Institute, Wuhan University, Wuhan 430072, China
| | - Shi Chen
- Key Laboratory of Combinatorial Biosynthesis and Drug Discovery of Ministry of Education, School of Pharmaceutical Sciences, and Brain Center, Zhongnan Hospital, and Medical Research Institute, Wuhan University, Wuhan 430072, China
| |
Collapse
|
|
37
|
Yang L, Lv Z, Xia W, Zhang W, Xin Y, Yuan H, Chen Y, Hu X, Lv Y, Xu Q, Weng X, Ni C. The effect of aspirin on circulating tumor cells in metastatic colorectal and breast cancer patients: a phase II trial study. Clin Transl Oncol 2017; 20:912-921. [PMID: 29243075 DOI: 10.1007/s12094-017-1806-z] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2017] [Accepted: 11/09/2017] [Indexed: 12/13/2022]
Abstract
PURPOSE Aspirin could reduce the risk of cancer metastasis. Circulating tumor cells (CTCs) are a key factor of cancer metastasis, but no evidence has revealed how aspirin affects CTCs and its epithelial-mesenchymal transition (EMT). Here, we conducted a clinical trial to investigate how aspirin affects CTCs in metastatic colorectal cancer (MCC) and breast cancer patients (MBC). METHODS The trial is retrospective registered at clinicaltrials.gov (NCT02602938). The eligible patients are given 100 mg aspirin q.d. for 8 weeks, and CTCs are evaluated at baseline, 4 and 8 weeks for absolute number, phenotype (epithelial type, E+, mesenchymal type, M+, and biophenotypic type, B+), and vimentin expression. RESULTS Data on 21 MCC and 19 MBC patients are analyzed, and it revealed that the CTC numbers decreased with aspirin treatment in MCC (p < 0.001) but not MBC (p = 0.0532); besides, ratio of E+ CTCs increased (p = 0.037) and M+ CTCs decreased at 2 months in MCC (p = 0.013), but neither the ratio of E+ or M+ CTCs changes significantly in MBC; vimentin expression of M+ CTCs is higher than E+ and B+ CTCs either in MBC or MCC patients at baseline (p < 0.01); and aspirin suppresses the vimentin expression in M+ (p = 0.002)and B+ (p = 0.006) CTCs of MCC and M+ CTCs of MBC (p = 0.004); besides it find vimentin expression in B+ (p = 0.004) or M+ (p < 0.001), CTCs are markedly decreased in patients with total CTC numbers declined. CONCLUSION Aspirin could decrease CTCs numbers and block EMT transition in MCC patients and part of MBC patients.
Collapse
Affiliation(s)
- L Yang
- Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Key Laboratory of Gastroenterology of Zhejiang Province, Zhejiang Provincial People's Hospital, Hangzhou Medicine College, Hangzhou, 310014, Zhejiang, People's Republic of China
| | - Z Lv
- Department of Breast and Thyroid Surgery, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, 310014, Zhejiang, People's Republic of China
| | - W Xia
- Department of Breast and Thyroid Surgery, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, 310014, Zhejiang, People's Republic of China
| | - W Zhang
- Department of Endocrinology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, 310014, People's Republic of China
| | - Y Xin
- Department of Breast and Thyroid Surgery, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, 310014, Zhejiang, People's Republic of China
| | - H Yuan
- Department of Breast and Thyroid Surgery, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, 310014, Zhejiang, People's Republic of China
| | - Y Chen
- Department of Oncology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, 310014, Zhejiang, People's Republic of China
| | - X Hu
- Department of Anus and Intestine Surgery, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, 310014, Zhejiang, People's Republic of China
| | - Y Lv
- SurExam Bio-Tech, Guangzhou Technology Innovation Base, Science City, Guangzhou, People's Republic of China
| | - Q Xu
- Department of Breast and Thyroid Surgery, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, 310014, Zhejiang, People's Republic of China
| | - X Weng
- Department of General Surgery, Central Hospital of Haining, Zhejiang, 310000, People's Republic of China
| | - C Ni
- Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Key Laboratory of Gastroenterology of Zhejiang Province, Zhejiang Provincial People's Hospital, Hangzhou Medicine College, Hangzhou, 310014, Zhejiang, People's Republic of China. .,Department of Breast and Thyroid Surgery, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, 310014, Zhejiang, People's Republic of China.
| |
Collapse
|