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Khalili-Tanha G, Khalili-Tanha N, Rouzbahani AK, Mahdieh R, Jasemi K, Ghaderi R, Leylakoohi FK, Ghorbani E, Khazaei M, Hassanian SM, Gataa IS, Ferns GA, Nazari E, Avan A. Diagnostic, prognostic, and predictive biomarkers in gastric cancer: from conventional to novel biomarkers. Transl Res 2024; 274:35-48. [PMID: 39260559 DOI: 10.1016/j.trsl.2024.09.001] [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: 03/10/2024] [Revised: 08/12/2024] [Accepted: 09/04/2024] [Indexed: 09/13/2024]
Abstract
Gastric cancer is a major health concern worldwide. The survival rate of Gastric cancer greatly depends on the stage at which it is diagnosed. Early diagnosis is critical for improving survival outcomes. To improve the chances of early diagnosis, regular screening tests, such as an upper endoscopy or barium swallow, are recommended for individuals at a higher risk due to factors like family history or a previous diagnosis of gastric conditions. Biomarkers can be detected and measured using non-invasive methods such as blood tests, urine tests, breath analysis, or imaging techniques. These non-invasive approaches offer many advantages, including convenience, safety, and cost-effectiveness, making them valuable tools for disease diagnosis, monitoring, and research. Biomarker-based tests have emerged as a useful tool for identifying gastric cancer early, monitoring treatment response, assessing the recurrence risk, and personalizing treatment plans. In this current review, we have explored both classical and novel biomarkers for gastric cancer. We have centralized their potential clinical application and discussed the challenges in Gastric cancer research.
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Affiliation(s)
- Ghazaleh Khalili-Tanha
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Nima Khalili-Tanha
- Department of Small Animal Clinical Sciences, Western College of Veterinary Medicine, University of Saskatchewan, 52 Campus Drive, Saskatoon, SK S7N 5B4, Canada
| | | | - Ramisa Mahdieh
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Kimia Jasemi
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Rosa Ghaderi
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Elnaz Ghorbani
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Majid Khazaei
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed Mahdi Hassanian
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Gordon A Ferns
- Brighton & Sussex Medical School, Department of Medical Education, Falmer, Brighton, Sussex BN1 9PH, UK
| | - Elham Nazari
- Proteomics Research Center, Faculty of Paramedical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Amir Avan
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Faculty of Health, School of Biomedical Sciences, Queensland University of Technology, Brisbane, Australia.
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Zou Y, Yuan Y, Zhou Q, Yue Z, Liu J, Fan L, Xu H, Xin L. The Role of Methionine Restriction in Gastric Cancer: A Summary of Mechanisms and a Discussion on Tumor Heterogeneity. Biomolecules 2024; 14:161. [PMID: 38397398 PMCID: PMC10887009 DOI: 10.3390/biom14020161] [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: 12/09/2023] [Revised: 01/18/2024] [Accepted: 01/24/2024] [Indexed: 02/25/2024] Open
Abstract
Gastric cancer is ranked as the fifth most prevalent cancer globally and has long been a topic of passionate discussion among numerous individuals. However, the incidence of gastric cancer in society has not decreased, but instead has shown a gradual increase in recent years. For more than a decade, the treatment effect of gastric cancer has not been significantly improved. This is attributed to the heterogeneity of cancer, which makes popular targeted therapies ineffective. Methionine is an essential amino acid, and many studies have shown that it is involved in the development of gastric cancer. Our study aimed to review the literature on methionine and gastric cancer, describing its mechanism of action to show that tumor heterogeneity in gastric cancer does not hinder the effectiveness of methionine-restricted therapies. This research also aimed to provide insight into the inhibition of gastric cancer through metabolic reprogramming with methionine-restricted therapies, thereby demonstrating their potential as adjuvant treatments for gastric cancer.
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Affiliation(s)
| | | | | | | | | | | | | | - Lin Xin
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, No. 1 Minde Road, Donghu District, Nanchang 330006, China; (Y.Z.); (Y.Y.); (Q.Z.); (Z.Y.); (J.L.); (L.F.); (H.X.)
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El Mashad SN, Kandil MAEH, Talab TAEH, Saied Abd El Naby AEN, Sultan MM, Sohaib A, Hemida AS. Gastric Carcinoma with low ROR alpha, low E- Cadherin and High LAPTM4B Immunohistochemical Profile; is associated with unfavorable prognosis in Egyptian patients. J Immunoassay Immunochem 2024; 45:50-72. [PMID: 38031398 DOI: 10.1080/15321819.2023.2279639] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2023]
Abstract
In view of multiplicity of carcinogenic pathways of gastric carcinoma (GC), poor survival and chemotherapy resistance, more analysis of these pathways is required for prediction of prognosis and developing new therapeutic targets. Knocking down of RORα; induces tumor cell proliferation and epithelial-mesenchymal transition (EMT). LAPTM4B has been suggested to be associated with EMT which promote tumor invasion. This work aimed to investigate prognostic role of RORα, LAPTM4B, and E-Cadherin expression in GC. This retrospective immunohistochemical study assesses the expression of RORα, LAPTM4B, and E-Cadherin in 73 primary gastric carcinomas. Low RORα and high LAPTM4B expression in GC cases were associated with unfavorable prognostic factors such as positive lymph nodes, and high tumor budding. E-Cadherin heterogeneous staining was associated with poor prognostic criteria, such as diffuse type GC and high tumor budding. Low RORα, high LAPTM4B, and heterogeneous E-Cadherin were the most common immunohistochemical profile in GC cases. Low RORα expression showed poor prognostic impact on overall patient survival. In conclusion, RORα and LAPTM4B may have crucial role in GC aggressiveness. The predominance of low RORα, high LAPTM4B, and heterogeneous or negative E-Cadherin immunohistochemical profile in GC cases with unfavorable pathological parameters suggested that this profile may predict tumor behavior.
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Affiliation(s)
| | | | | | | | - Mervat Mahmoud Sultan
- Pathology Department, National Liver Institute, Menoufia University, Shebin El Kom, Egypt
| | - Ahmed Sohaib
- Clinical Oncology& Nuclear medicine Department, Faculty of Medicine, Menoufia University, Shebin El Kom, Egypt
| | - Aiat Shaban Hemida
- Pathology Department, Faculty of Medicine, Menoufia University, Shebin El Kom, Egypt
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Dolbnya AD, Popov IA, Pekov SI. Molecular Biomarkers in Cholangiocarcinoma: Focus on Bile. Curr Top Med Chem 2024; 24:722-736. [PMID: 38303538 DOI: 10.2174/0115680266290367240130054142] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 01/12/2024] [Accepted: 01/17/2024] [Indexed: 02/03/2024]
Abstract
Hepatobiliary system cancers have demonstrated an increasing incidence rate in the past years. Without the presence of early symptoms, the majority of such cancers manifest with a set of similar symptoms, such as cholestasis resulting in posthepatic icterus. Differential diagnosis of hepatobiliary cancers is required for the therapy selection, however, the similarity of the symptoms complicates diagnostics. Thus, the search for molecular markers is of high interest for such patients. Cholangiocarcinoma (CCA) is characterized by a poor prognosis due to a low resectability rate, which occurs because this disease is frequently beyond the limits of surgical therapy at the time of diagnosis. The CCA is diagnosed by the combination of clinical/biochemical features, radiological methods, and non-specific serum tumor biomarkers, although invasive examination is still needed. The main disadvantage is limited specificity and sensitivity, which complicates early diagnostics. Therefore, prognostic and predictive biomarkers are still lacking and urgently needed for early diagnosis. In contrast to serum, bile is more accessible to identify biliary disease due to its simpler composition. Moreover, bile can contain higher concentrations of tumor biomarkers due to its direct contact with the tumor. It is known that the composition of the main bile component - bile acids, may vary during different diseases of the biliary tract. This review summarizes the recent developments in the current research on the diagnostic biomarkers for CCA in serum and bile and provides an overview of the methods of bile acids analysis.
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Affiliation(s)
- Andrey D Dolbnya
- Siberian State Medical University, Tomsk, 634050, Russian Federation
| | - Igor A Popov
- Siberian State Medical University, Tomsk, 634050, Russian Federation
- Moscow Institute of Physics and Technology, Dolgoprudny, 141701, Russian Federation
| | - Stanislav I Pekov
- Siberian State Medical University, Tomsk, 634050, Russian Federation
- Moscow Institute of Physics and Technology, Dolgoprudny, 141701, Russian Federation
- Skolkovo Institute of Science and Technology, Moscow, 121205, Russian Federation
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Qin YC, Yan X, Yuan XL, Yu WW, Qu FJ. Osteopontin promotes gastric cancer progression via phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin signaling pathway. World J Gastrointest Oncol 2023; 15:1544-1555. [PMID: 37746644 PMCID: PMC10514723 DOI: 10.4251/wjgo.v15.i9.1544] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Revised: 07/14/2023] [Accepted: 07/28/2023] [Indexed: 09/13/2023] Open
Abstract
BACKGROUND Gastric cancer (GC) is one of the most common malignant tumors. Osteopontin (OPN) is thought to be closely related to the occurrence, metastasis and prognosis of many types of tumors. AIM To investigate the effects of OPN on the proliferation, invasion and migration of GC cells and its possible mechanism. METHODS The mRNA and protein expression of OPN in the GC cells were analyzed by real-time quantitative-reverse transcription polymerase chain reaction and western blotting, and observe the effect of varying degree expression OPN on the proliferation and other behaviors of GC. Next, the effects of OPN knockdown on GC cells migration and invasion were examined. The short hairpin RNA (shRNA) and negative control shRNA targeting OPN-shRNA were transfected into the cells according to the manufacturer's instructions. Non transfected cells were classified as control in the identical transfecting process. 24 h after RNA transfection cell proliferation activity was detected by 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide assay, and cell invasiveness and migration were detected by Trans well assay. Meanwhile, the expression of protein kinase B (AKT), matrix metalloproteinase 2 (MMP-2) and vascular endothelial growth factor (VEGF) in the human GC cell lines was detected by reverse transcription polymerase chain reaction and western blotting. RESULTS The results of this study revealed that OPN mRNA and protein expression levels were highly expressed in SGC-7901 cells. OPN knockdown by specific shRNA noticeably reduced the capabilities of proliferation, invasion and migration of SGC-7901 cells. Moreover, in the experiments of investigating the underlying mechanism, results showed that OPN knockdown could down-regulated the expression of MMP-2 and VEGF, it also decreased the phosphorylation of AKT. Meanwhile, the protein expression levels of MMP-2, VEGF and phosphorylated AKT was noticeable lower than that in control group in the GC cells after they were added to phosphatidylinositol-3-kinase (PI3K) inhibitor (LY294002). CONCLUSION These results suggested that OPN though PI3K/AKT/mammalian target of rapamycin signal pathway to up-regulate MMP-2 and VEGF expression, which contribute SGC-7901 cells to proliferation, invasion and migration. Thus, our results demonstrate that OPN may serve as a novel prognostic biomarkers as well as a potential therapeutic targets for GC.
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Affiliation(s)
- Yue-Chao Qin
- Department of Oncology, Affiliated Dalian Third People’s Hospital of Dalian Medical University, Dalian 116033, Liaoning Province, China
- Research Center, Affiliated Zhongshan Hospital of Dalian University, Dalian 116001, Liaoning Province, China
| | - Xin Yan
- Department of Oncology, Affiliated Dalian Third People’s Hospital of Dalian Medical University, Dalian 116033, Liaoning Province, China
| | - Xiao-Lin Yuan
- Research Center, Affiliated Zhongshan Hospital of Dalian University, Dalian 116001, Liaoning Province, China
| | - Wei-Wei Yu
- Department of Oncology, Affiliated Dalian Third People’s Hospital of Dalian Medical University, Dalian 116033, Liaoning Province, China
| | - Fan-Jie Qu
- Department of Oncology, Affiliated Dalian Third People’s Hospital of Dalian Medical University, Dalian 116033, Liaoning Province, China
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Osteopontin: A Bone-Derived Protein Involved in Rheumatoid Arthritis and Osteoarthritis Immunopathology. Biomolecules 2023; 13:biom13030502. [PMID: 36979437 PMCID: PMC10046882 DOI: 10.3390/biom13030502] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 02/24/2023] [Accepted: 03/07/2023] [Indexed: 03/12/2023] Open
Abstract
Osteopontin (OPN) is a bone-derived phosphoglycoprotein related to physiological and pathological mechanisms that nowadays has gained relevance due to its role in the immune system response to chronic degenerative diseases, including rheumatoid arthritis (RA) and osteoarthritis (OA). OPN is an extracellular matrix (ECM) glycoprotein that plays a critical role in bone remodeling. Therefore, it is an effector molecule that promotes joint and cartilage destruction observed in clinical studies, in vitro assays, and animal models of RA and OA. Since OPN undergoes multiple modifications, including posttranslational changes, proteolytic cleavage, and binding to a wide range of receptors, the mechanisms by which it produces its effects, in some cases, remain unclear. Although there is strong evidence that OPN contributes significantly to the immunopathology of RA and OA when considering it as a common denominator molecule, some experimental trial results argue for its protective role in rheumatic diseases. Elucidating in detail OPN involvement in bone and cartilage degeneration is of interest to the field of rheumatology. This review aims to provide evidence of the OPN’s multifaceted role in promoting joint and cartilage destruction and propose it as a common denominator of AR and OA immunopathology.
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Xie W, Cheng J, Hong Z, Cai W, Zhuo H, Hou J, Lin L, Wei X, Wang K, Chen X, Song Y, Wang Z, Cai J. Multi-Transcriptomic Analysis Reveals the Heterogeneity and Tumor-Promoting Role of SPP1/CD44-Mediated Intratumoral Crosstalk in Gastric Cancer. Cancers (Basel) 2022; 15:cancers15010164. [PMID: 36612160 PMCID: PMC9818284 DOI: 10.3390/cancers15010164] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Revised: 12/20/2022] [Accepted: 12/25/2022] [Indexed: 12/29/2022] Open
Abstract
GC is a fatal disease with high heterogeneity and invasiveness. Recently, SPP1 has been reported to be involved in the tumor progression of multiple human cancers; however, the role of SPP1 in GC heterogeneity and whether it is associated with the invasiveness and mortality of GC remain unclear. Here, we combined multiple RNA sequencing approaches to evaluate the impact of SPP1 on GC. Through bulk RNA sequencing (bulk RNA-seq) and immunohistochemistry (IHC), we found that SPP1 was highly expressed in GC, and high levels of SPP1 were associated with macrophage infiltration, an advanced tumor stage, and higher mortality for advanced GC patients. Furthermore, through simultaneous single-cell and spatial analysis, we demonstrated that SPP1+ macrophages are tumor-specific macrophages unique to cancer and enriched in the deep layer of GC tissue. Cell-cell communication analysis revealed that SPP1/CD44 interactions between SPP1+ macrophages and their localized tumor epithelial cells could activate downstream target genes in epithelial cells to promote dynamic changes in intratumor heterogeneity. Moreover, these activated genes were found to be closely associated with poor clinical GC outcomes and with cancer-related pathways that promote GC progression, as shown by survival analysis and enrichment analysis, respectively. Collectively, our study reveals that tumor-specific SPP1+ macrophages drive the architecture of intratumor heterogeneity to evolve with tumor progression and that SPP1 may serve as a prognostic marker for advanced GC patients, as well as a potential therapeutic target for GC.
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Affiliation(s)
- Wen Xie
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361001, China
- Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen 361001, China
| | - Jia Cheng
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361001, China
- Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen 361001, China
| | - Zhijun Hong
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361001, China
- Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen 361001, China
| | - Wangyu Cai
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361001, China
- Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen 361001, China
| | - Huiqin Zhuo
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361001, China
- Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen 361001, China
| | - Jingjing Hou
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361001, China
- Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen 361001, China
| | - Lingyun Lin
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361001, China
- Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen 361001, China
| | - Xujin Wei
- The Graduate School of Fujian Medical University, Fuzhou 350004, China
| | - Kang Wang
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361001, China
- Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen 361001, China
| | - Xin Chen
- The Graduate School of Fujian Medical University, Fuzhou 350004, China
| | - Yucheng Song
- The Graduate School of Fujian Medical University, Fuzhou 350004, China
| | - Zhenfa Wang
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361001, China
- Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen 361001, China
| | - Jianchun Cai
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361001, China
- Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen 361001, China
- The Graduate School of Fujian Medical University, Fuzhou 350004, China
- Correspondence:
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Bispo IMC, Granger HP, Almeida PP, Nishiyama PB, de Freitas LM. Systems biology and OMIC data integration to understand gastrointestinal cancers. World J Clin Oncol 2022; 13:762-778. [PMID: 36337313 PMCID: PMC9630993 DOI: 10.5306/wjco.v13.i10.762] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 05/22/2021] [Accepted: 10/02/2022] [Indexed: 02/06/2023] Open
Abstract
Gastrointestinal (GI) cancers are a set of diverse diseases affecting many parts/ organs. The five most frequent GI cancer types are esophageal, gastric cancer (GC), liver cancer, pancreatic cancer, and colorectal cancer (CRC); together, they give rise to 5 million new cases and cause the death of 3.5 million people annually. We provide information about molecular changes crucial to tumorigenesis and the behavior and prognosis. During the formation of cancer cells, the genomic changes are microsatellite instability with multiple chromosomal arrangements in GC and CRC. The genomically stable subtype is observed in GC and pancreatic cancer. Besides these genomic subtypes, CRC has epigenetic modification (hypermethylation) associated with a poor prognosis. The pathway information highlights the functions shared by GI cancers such as apoptosis; focal adhesion; and the p21-activated kinase, phosphoinositide 3-kinase/Akt, transforming growth factor beta, and Toll-like receptor signaling pathways. These pathways show survival, cell proliferation, and cell motility. In addition, the immune response and inflammation are also essential elements in the shared functions. We also retrieved information on protein-protein interaction from the STRING database, and found that proteins Akt1, catenin beta 1 (CTNNB1), E1A binding protein P300, tumor protein p53 (TP53), and TP53 binding protein 1 (TP53BP1) are central nodes in the network. The protein expression of these genes is associated with overall survival in some GI cancers. The low TP53BP1 expression in CRC, high EP300 expression in esophageal cancer, and increased expression of Akt1/TP53 or low CTNNB1 expression in GC are associated with a poor prognosis. The Kaplan Meier plotter database also confirmed the association between expression of the five central genes and GC survival rates. In conclusion, GI cancers are very diverse at the molecular level. However, the shared mutations and protein pathways might be used to understand better and reveal diagnostic/prognostic or drug targets.
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Affiliation(s)
- Iasmin Moreira Costa Bispo
- Núcleo de Biointegração, Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45.029-094, Bahia, Brazil
| | - Henry Paul Granger
- Núcleo de Biointegração, Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45.029-094, Bahia, Brazil
| | - Palloma Porto Almeida
- Division of Experimental and Translational Research, Brazilian National Cancer Institute, Rio de Janeiro 20231-050, Brazil
| | - Patricia Belini Nishiyama
- Núcleo de Biointegração, Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45.029-094, Bahia, Brazil
| | - Leandro Martins de Freitas
- Núcleo de Biointegração, Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45.029-094, Bahia, Brazil
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Mashad SNE, Kandil MAE, Talab TAE, Naby AENSAE, Sultan MM, Sohaib A, Hemida AS. Gastric Carcinoma with low ROR alpha, low E- Cadherin and High LAPTM4B Immunohistochemical Profile; is associated with poor prognosis in Egyptian patients.. [DOI: 10.21203/rs.3.rs-2123133/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/01/2023]
Abstract
Abstract
Background
Gastric carcinoma (GC) is the tenth most prevalent cancer in both sexes in Egypt. Many pathways have been investigated regarding pathogenesis of GC, including epithelial-mesenchymal transition (EMT) pathway. In view of multiplicity of carcinogenic pathways, poor survival and chemotherapy resistance detected in GC patients, more analysis of these pathways is required for better molecular selection of patients, prediction of prognosis and developing new therapeutic targets. Down-regulation of E-Cadherin is an important EMT stage. RORα is a tumor suppressor gene, expressed in normal epithelial tissues and reduced in a variety of human cancers. Knocking down of RORα; increase cell proliferation, EMT, migration, and invasion. LAPTM4B is a protooncogene and it has been suggested to be strictly associated with EMT induction. Therefore, this work aims to investigate the role of RORα, LAPTM4B and E-Cadherin and its relationship to prognosis of GC.
Methods
This is a retrospective study where the standard immunohistochemical technique was done to assess the expression of RORα, LAPTM4B and E-Cadherin in 167 cases of chronic gastritis (control group) and 73 primary gastric carcinomas (51 of them have available adjacent non tumor tissue).
Results
Low RORα and high LAPTM4B expression in GC cases were associated with unfavorable prognostic factors such as positive lymph nodes, and high tumor budding. E-Cadherin Heterogeneous staining was associated with poor prognostic pathological criteria, such as diffuse type GC and high tumor budding. In GC, there was significant co parallel correlation between RORα and E-Cadherin expression while LAPTM4B showed inverse correlation with E-Cadherin expression. Low RORα, high LAPTM4B, and negative or heterogeneous E-Cadherin were the most common immunohistochemical profile in GC cases. Low RORα expression showed poor prognostic impact on overall patient survival.
Conclusions
Low RORα H-score and increased expression of LAPTM4B were significantly associated with unfavorable prognostic parameters of GC which may indicate their crucial role in tumor aggressiveness. The predominance of low RORα, high LAPTM4B and heterogeneous or negative E-Cadherin immunohistochemical profile in GC cases with unfavorable pathological parameters suggested that this profile may predict tumor behavior and this profile could be linked to EMT molecular subtype of GC
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Xue S, Zheng T, Yan J, Ma J, Lin C, Dong S, Wei C, Li T, Zhang X, Li G. Identification of a 3-Gene Model as Prognostic Biomarker in Patients With Gastric Cancer. Front Oncol 2022; 12:930586. [PMID: 35912206 PMCID: PMC9329618 DOI: 10.3389/fonc.2022.930586] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 06/20/2022] [Indexed: 11/13/2022] Open
Abstract
ObjectiveAlthough the incidence of gastric cancer (GC) is decreasing, GC remains one of the leading cancers in the world. Surgical resection, radiotherapy, chemotherapy, and neoadjuvant therapy have advanced, but patients still face the risk of recurrence and poor prognosis. This study provides new insights for assessment of prognosis and postoperative recurrence of GC patients.MethodsWe collected paired cancer and adjacent tissues of 17 patients with early primary GC for bulk transcriptome sequencing. By comparing the transcriptome information of cancer and adjacent cancer, 321 differentially expressed genes (DEGs) were identified. These DEGs were further screened and analyzed with the GC cohort of TCGA to establish a 3-gene prognostic model (PLCL1, PLOD2 and ABCA6). At the same time, the predictive ability of this risk model is validated in multiple public data sets. Besides, the differences in immune cells proportion between the high- and low-risk groups were analyzed by the CIBERSORT algorithm with the Leukocyte signature matrix (LM22) gene signature to reveal the role of the immune microenvironment in the occurrence and development of GC.ResultsThe model could divide GC samples from TCGA cohorts into two groups with significant differences in overall and disease-free survival. The excellent predictive ability of this model was also validated in multiple other public data sets. The proportion of these immune cells such as resting mast cells, T cells CD4+ memory activated and Macrophages M2 are significantly different between high and low risk group.ConclusionThese three genes used to build the models were validated as biomarkers for predicting tumor recurrence and survival. They may have potential significance for the treatment and diagnosis of patients in the future, and may also promote the development of targeted drugs.
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Affiliation(s)
- Siming Xue
- Beijing Genomics Institute (BGI)-Shenzhen, Shenzhen, China
- Beijing Genomics Institute (BGI)-Henan, BGI-Shenzhen, Xinxiang, China
| | - Tianjiao Zheng
- Beijing Genomics Institute (BGl) College & Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China
| | - Juan Yan
- Beijing Genomics Institute (BGl) College & Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China
| | - Jinmin Ma
- Beijing Genomics Institute (BGI)-Shenzhen, Shenzhen, China
| | - Cong Lin
- Beijing Genomics Institute (BGI)-Shenzhen, Shenzhen, China
| | - Shichen Dong
- Beijing Genomics Institute (BGI)-Shenzhen, Shenzhen, China
- Beijing Genomics Institute (BGI)-Henan, BGI-Shenzhen, Xinxiang, China
| | - Chen Wei
- Beijing Genomics Institute (BGI)-Shenzhen, Shenzhen, China
- Beijing Genomics Institute (BGI)-Henan, BGI-Shenzhen, Xinxiang, China
| | - Tong Li
- Beijing Genomics Institute (BGI)-Shenzhen, Shenzhen, China
- Beijing Genomics Institute (BGI)-Henan, BGI-Shenzhen, Xinxiang, China
| | - Xiaoyin Zhang
- Department of Gastroenterology, National Clinical Research Center of Infectious Disease, The Third People’s Hospital of Shenzhen, The Second Affiliated Hospital of Southern University of Science and Technology, Shenzhen, China
- *Correspondence: Guibo Li, ; Xiaoyin Zhang,
| | - Guibo Li
- Beijing Genomics Institute (BGI)-Shenzhen, Shenzhen, China
- Beijing Genomics Institute (BGI)-Henan, BGI-Shenzhen, Xinxiang, China
- *Correspondence: Guibo Li, ; Xiaoyin Zhang,
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Novel Biomarkers of Gastric Adenocarcinoma: Current Research and Future Perspectives. Cancers (Basel) 2021; 13:cancers13225660. [PMID: 34830815 PMCID: PMC8616337 DOI: 10.3390/cancers13225660] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2021] [Revised: 11/05/2021] [Accepted: 11/09/2021] [Indexed: 12/13/2022] Open
Abstract
Simple Summary Gastric cancer is characterized by poor survival rates despite surgery and chemotherapy. Current research focuses on biomarkers to improve diagnosis and prognosis, and to enable targeted treatment strategies. The aim of our review was to give an overview over the wide range of novel biomarkers in gastric cancer. These biomarkers are targets of a specific treatment, such as antibodies against human epidermal growth factor receptor 2. Other promising biomarkers for targeted therapies that have shown relevance in clinical trials are vascular endothelial growth factor, programmed cell death protein 1, and Claudin 18.2. There is a vast number of biomarkers based on DNA, RNA, and protein expression, as well as detection of circulating tumor cells and the immune tumor microenvironment. Abstract Overall survival of gastric cancer remains low, as patients are often diagnosed with advanced stage disease. In this review, we give an overview of current research on biomarkers in gastric cancer and their implementation in treatment strategies. The HER2-targeting trastuzumab is the first molecular targeted agent approved for gastric cancer treatment. Other promising biomarkers for targeted therapies that have shown relevance in clinical trials are VEGF and Claudin 18.2. Expression of MET has been shown to be a negative prognostic factor in gastric cancer. Targeting the PD-1/PD-L1 pathway with immune checkpoint inhibitors has proven efficacy in advanced gastric cancer. Recent technology advances allow the detection of circulating tumor cells that may be used as diagnostic and prognostic indicators and for therapy monitoring in gastric cancer patients. Prognostic molecular subtypes of gastric cancer have been identified using genomic data. In addition, transcriptome profiling has allowed a comprehensive characterization of the immune and stromal microenvironment in gastric cancer and development of novel risk scores. These prognostic and predictive markers highlight the rapidly evolving field of research in gastric cancer, promising improved treatment stratification and identification of molecular targets for individualized treatment in gastric cancer.
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12
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Yang X, Wen Y, Song X, He S, Bo X. Exploring the classification of cancer cell lines from multiple omic views. PeerJ 2020; 8:e9440. [PMID: 32874774 PMCID: PMC7441922 DOI: 10.7717/peerj.9440] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Accepted: 06/08/2020] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Cancer classification is of great importance to understanding its pathogenesis, making diagnosis and developing treatment. The accumulation of extensive omics data of abundant cancer cell line provide basis for large scale classification of cancer with low cost. However, the reliability of cell lines as in vitro models of cancer has been controversial. METHODS In this study, we explore the classification on pan-cancer cell line with single and integrated multiple omics data from the Cancer Cell Line Encyclopedia (CCLE) database. The representative omics data of cancer, mRNA data, miRNA data, copy number variation data, DNA methylation data and reverse-phase protein array data were taken into the analysis. TumorMap web tool was used to illustrate the landscape of molecular classification.The molecular classification of patient samples was compared with cancer cell lines. RESULTS Eighteen molecular clusters were identified using integrated multiple omics clustering. Three pan-cancer clusters were found in integrated multiple omics clustering. By comparing with single omics clustering, we found that integrated clustering could capture both shared and complementary information from each omics data. Omics contribution analysis for clustering indicated that, although all the five omics data were of value, mRNA and proteomics data were particular important. While the classifications were generally consistent, samples from cancer patients were more diverse than cancer cell lines. CONCLUSIONS The clustering analysis based on integrated omics data provides a novel multi-dimensional map of cancer cell lines that can reflect the extent to pan-cancer cell lines represent primary tumors, and an approach to evaluate the importance of omic features in cancer classification.
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Affiliation(s)
- Xiaoxi Yang
- Department of Biotechnology, Beijing Institute of Radiation Medicine, Beijing, China
| | - Yuqi Wen
- Department of Biotechnology, Beijing Institute of Radiation Medicine, Beijing, China
| | - Xinyu Song
- Key Laboratory of Biomedical Engineering and Translational Medicine, Ministry of Industry and Information Technology, Chinese PLA General Hospital, Beijing, China
| | - Song He
- Department of Biotechnology, Beijing Institute of Radiation Medicine, Beijing, China
| | - Xiaochen Bo
- Department of Biotechnology, Beijing Institute of Radiation Medicine, Beijing, China
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Wang K, Li E, Busuttil RA, Kong JC, Pattison S, Sung JJY, Yu J, El-Omar EM, Simpson JA, Boussioutas A. A cohort study and meta-analysis of the evidence for consideration of Lauren subtype when prescribing adjuvant or palliative chemotherapy for gastric cancer. Ther Adv Med Oncol 2020; 12:1758835920930359. [PMID: 32754227 PMCID: PMC7378722 DOI: 10.1177/1758835920930359] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Accepted: 04/24/2020] [Indexed: 12/13/2022] Open
Abstract
Background The association between the survival or efficacy of chemotherapy and the Lauren subtype of gastric cancer (GC) remains unclear. We aimed to clarify whether patients with different Lauren subtypes have different survival after treatment with systemic chemotherapy: intestinal gastric cancer (IGC) patients survived better than patients with mixed type gastric cancer (MGC) or diffuse gastric cancer (DGC) after treatment with systemic chemotherapy. Patients & methods Relevant studies for the meta-analysis were identified through searching Pubmed, Embase, Cochrane and Ovid up to March 2020. We also included our own prospectively collected cohort of patients that were followed over a 10-year period. Sub-group and sensitivity analyses were also performed. Results In our prospective cohort, the overall survival (OS) of IGC patients receiving systemic chemotherapy (chemoIGC) [median OS 5.01 years, interquartile range (IQR) 2.63-6.71] was significantly higher than that of DGC patients receiving the same chemotherapy (chemoDGC) (median OS 1.33 years, IQR 0.78-3.33, p = 0.0001). After adjusting for age, gender and cancer stage, there was a significant difference in OS in patients treated with chemotherapy based on the Lauren classification of GC {hazard ratio (HR) for OS of the IGC versus DGC 0.33, [95% confidence interval (CI), 0.17-0.65; p < 0.001]}. In the IGC patients, the adjusted HR associated with chemotherapy was 0.26 (95% CI, 0.12-0.56; p = 0.001), whereas the association was 0.64 (95% CI, 0.30-1.33; p = 0.23) in the DGC patient group.In our meta-analysis, 33 studies comprising 10,246 patients treated with systemic chemotherapy (chemoIGC n = 4888, chemoDGC n = 5358) met all the selection criteria. While we accounted for much of the heterogeneity in these studies, we found that chemoIGC patients showed significantly improved OS [HR, 0.76 (95% CI, 0.71-0.82); p < 0.00001] when compared with similarly treated chemoDGC patients. Conclusion Our results support the consideration of Lauren subtype when prescribing systemic chemotherapy for GC, particularly for MGC or DGC, which may not benefit from chemotherapy. Lauren classification should be considered to stratify chemotherapy regimens to GC patients in future clinical trials, with particular relevance to MGC or DGC, which is more difficult to treat with current regimens.
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Affiliation(s)
- Kunning Wang
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, P. R. China
| | - Enxiao Li
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, P. R. China
| | - Rita A Busuttil
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia
| | - Joseph C Kong
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia
| | - Sharon Pattison
- Department of Medicine, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
| | - Joseph J Y Sung
- Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Institute of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Jun Yu
- Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Institute of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Emad M El-Omar
- Department of Medicine, St George & Sutherland Clinical School, University of New South Wales, Sydney, NSW, Australia
| | - Julie A Simpson
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia
| | - Alex Boussioutas
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia
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14
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Di Bartolomeo M, Raimondi A, Cecchi F, Catenacci DVT, Schwartz S, Sellappan S, Tian Y, Miceli R, Pellegrinelli A, Giommoni E, Aitini E, Spada F, Rosati G, Marchet A, Pucci F, Zaniboni A, Tamberi S, Pressiani T, Sanna G, Cantore M, Mosconi S, Bolzoni P, Pinto C, Landi L, Soto Parra HJ, Cavanna L, Corallo S, Martinetti A, Hembrough TA, Pietrantonio F. Association of high TUBB3 with resistance to adjuvant docetaxel-based chemotherapy in gastric cancer: translational study of ITACA-S. TUMORI JOURNAL 2020; 107:150-159. [PMID: 32522106 DOI: 10.1177/0300891620930803] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
BACKGROUND No predictive markers for chemotherapy activity have been validated in gastric cancer (GC). The potential value of class III β-tubulin (TUBB3) as biomarker for prognosis and resistance to taxane-based therapy was reported. METHODS We analyzed GC samples of patients enrolled in the Intergroup Trial of Adjuvant Chemotherapy in Adenocarcinoma of the Stomach (ITACA-S), a randomized adjuvant study comparing 5-fluorouracil/leucovorin (5-FU/LV) and docetaxel-based sequential chemotherapy. TUBB3 was quantitated by selected reaction monitoring mass spectrometry and patients were stratified using a threshold of 750 attomoles per microgram (amol/µg). Cox proportional modeling and Kaplan-Meier survival analysis were used to assess the impact of TUBB3 expression on overall survival (OS) and disease-free survival. RESULTS Patients with TUBB3 protein levels >750 and <750 amol/µg were 21.9% and 78.1%, respectively, and were well-balanced between treatment arms. TUBB3 protein levels were not prognostic. Whereas no survival differences according to the 2 arms were observed in the subgroup with low TUBB3 expression (5-year OS 47% vs 40%; p = 0.44), patients with high TUBB3 had a clinically meaningful poorer OS when receiving docetaxel-based versus 5-FU/LV chemotherapy (5-year OS 31% vs 54%; p = 0.09), with a statistically significant interaction between TUBB3 and treatment (p = 0.049). CONCLUSIONS The quantification of TUBB3 might be considered as a negative predictive biomarker of benefit from taxane-based therapy in GC. Studies are needed to evaluate its role in the neoadjuvant setting.
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Affiliation(s)
- Maria Di Bartolomeo
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Alessandra Raimondi
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | | | | | | | | | | | - Rosalba Miceli
- Department of Medical Statistics, Biometry, and Bioinformatics, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | | | - Elisa Giommoni
- Medical Oncology, Azienda Ospedaliera-Università Careggi, Firenze, Italy
| | - Enrico Aitini
- Medical Oncology, Ospedale di Suzzara, Mantova, Italy
| | - Francesca Spada
- Gastrointestinal Oncology and Neuroendocrine Tumors, Istituto Oncologico Europeo, Milan, Italy
| | - Gerardo Rosati
- Medical Oncology, Azienda Ospedaliera "San Carlo," Potenza, Italy
| | - Alberto Marchet
- Surgery, Oncology and Gastroenterology Department, Azienda Ospedaliera di Padova, Padova, Italy
| | - Francesca Pucci
- Medical Oncology, Azienda Ospedaliera di Parma, Parma, Italy
| | - Alberto Zaniboni
- Oncology Department, Istituto Ospedaliero Fondazione Poliambulanza, Brescia, Italy
| | | | - Tiziana Pressiani
- Medical Oncology and Hematology, Istituto Clinico Humanitas, Rozzano, Milan, Italy
| | - Gianni Sanna
- Medical Oncology, Istituto Ospedaliero dell'Università di Sassari, Sassari, Italy
| | - Maurizio Cantore
- Medical Oncology, Azienda Ospedaliera "Carlo Poma," Mantova, Italy
| | | | - Paola Bolzoni
- Medical Oncology, Presidio Ospedaliero "Serbelloni" di Gorgonzola, Melegnano, Italy
| | - Carmine Pinto
- Medical Oncology, Arcispedale Santa Maria Nuova Azienda Ospedaliera di Reggio Emilia, Reggio Emilia, Italy
| | - Lorenza Landi
- Medical Oncology, Presidio Ospedaliero di Livorno, Livorno, Italy
| | - Hector Josè Soto Parra
- Medical Oncology, Policlinico Vittorio Emanuele, Presidio Gaspare Rodolico, Catania, Italy
| | - Luigi Cavanna
- Oncology-Hematology Department, Ospedale Civile "Guglielmo da Saliceto," Piacenza, Italy
| | - Salvatore Corallo
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Antonia Martinetti
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | | | - Filippo Pietrantonio
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.,Department of Oncology and Hemato-oncology, University of Milan, Milan, Italy
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15
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Di Bartolomeo M, Morano F, Raimondi A, Miceli R, Corallo S, Tamborini E, Perrone F, Antista M, Niger M, Pellegrinelli A, Randon G, Pagani F, Martinetti A, Fucà G, Pietrantonio F. Prognostic and Predictive Value of Microsatellite Instability, Inflammatory Reaction and PD-L1 in Gastric Cancer Patients Treated with Either Adjuvant 5-FU/LV or Sequential FOLFIRI Followed by Cisplatin and Docetaxel: A Translational Analysis from the ITACA-S Trial. Oncologist 2020; 25:e460-e468. [PMID: 32162808 PMCID: PMC7066701 DOI: 10.1634/theoncologist.2019-0471] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Accepted: 10/16/2019] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Patients with high microsatellite instability (MSI) gastric cancer (GC) show improved survival and no benefit or harm from adjuvant and/or perioperative chemotherapy. The role of immune microenvironment in GC is largely unknown. MATERIALS AND METHODS In the present study, 256 tumor tissue blocks were centrally collected from patients enrolled in ITACA-S, a randomized adjuvant trial of 5-FU/LV versus sequential FOLFIRI and cisplatin-docetaxel. MSI status was assessed by multiplex PCR, inflammatory reaction by H&E morphological assessment, and programmed death-ligand 1 (PD-L1) expression by immunohistochemistry. RESULTS Overall, 9% patients had MSI-high tumors, 23% had high inflammatory reaction, 11% had tumor PD-L1 ≥ 1%, and 11% had stromal PD-L1 ≥ 1%. A significant association with disease-free survival (DFS) and overall survival (OS) was found for MSI-high (hazard ratio [HR], 0.43; p = .02; HR, 0.40; p = .02) and high inflammatory reaction (HR, 0.55; p = .010; HR, 0.53; p = .008) but not for PD-L1. At multivariable analysis, only MSI showed an independent association with both DFS (p = .02) and OS (p = .01), whereas inflammatory reaction showed an independent association only with OS (p = .04). Patients with tumor PD-L1 ≥ 1% had a significantly longer DFS in sequential chemotherapy than in than 5-FU/LV arm (interaction p = .04) and a trend for OS (interaction p = .12). CONCLUSION Our data suggest that MSI status could be a useful prognostic biomarker in patients with radically resected stage II-III GC and should be used as stratification factor in future trials. Tumor PD-L1 ≥ 1% should be further investigated as a potential predictor of benefit from intensive chemotherapy. IMPLICATIONS FOR PRACTICE In this post hoc analysis of patients with radically resected gastric cancer randomized to an intensive sequential chemotherapy regimen versus 5-FU/LV monotherapy as adjuvant treatment in the ITACA-S trial, MSI-high status was independently associated with better disease-free survival and overall survival (OS) and inflammatory reaction was independently associated with better OS. Moreover, tumor PD-L1 expression ≥1% was associated with greater benefit from intensive sequential chemotherapy compared with 5-fluorouracil plus leucovorin (5-FU/LV), whereas PD-L1 expression <1% was not, conditioning a statistically significant interaction between such biomarker and treatment arms. The meta-analysis of individual patients' data from available studies could yield data on the role of MSI status that could inform clinical decisions.
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Affiliation(s)
- Maria Di Bartolomeo
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di MilanoMilanItaly
| | - Federica Morano
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di MilanoMilanItaly
| | - Alessandra Raimondi
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di MilanoMilanItaly
| | - Rosalba Miceli
- Unit of Clinical Epidemiology and Trial Organization, Fondazione IRCCS Istituto Nazionale dei Tumori di MilanoMilanItaly
| | - Salvatore Corallo
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di MilanoMilanItaly
| | - Elena Tamborini
- Pathology Department, Fondazione IRCCS Istituto Nazionale dei Tumori di MilanoMilanItaly
| | - Federica Perrone
- Pathology Department, Fondazione IRCCS Istituto Nazionale dei Tumori di MilanoMilanItaly
| | - Maria Antista
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di MilanoMilanItaly
| | - Monica Niger
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di MilanoMilanItaly
| | | | - Giovanni Randon
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di MilanoMilanItaly
| | - Filippo Pagani
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di MilanoMilanItaly
| | - Antonia Martinetti
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di MilanoMilanItaly
| | - Giovanni Fucà
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di MilanoMilanItaly
| | - Filippo Pietrantonio
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di MilanoMilanItaly
- Department of Oncology and Hemato‐oncology, University of MilanMilanItaly
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16
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Nazmi A, Greer MJ, Hoek KL, Piazuelo MB, Weitkamp JH, Olivares-Villagómez D. Osteopontin and iCD8α Cells Promote Intestinal Intraepithelial Lymphocyte Homeostasis. THE JOURNAL OF IMMUNOLOGY 2020; 204:1968-1981. [PMID: 32102904 DOI: 10.4049/jimmunol.1901168] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Accepted: 01/23/2020] [Indexed: 12/19/2022]
Abstract
Intestinal intraepithelial lymphocytes (IEL) comprise a diverse population of cells residing in the epithelium at the interface between the intestinal lumen and the sterile environment of the lamina propria. Because of this anatomical location, IEL are considered critical components of intestinal immune responses. Indeed, IEL are involved in many different immunological processes, ranging from pathogen control to tissue stability. However, despite their critical importance in mucosal immune responses, very little is known about the homeostasis of different IEL subpopulations. The phosphoprotein osteopontin is important for critical physiological processes, including cellular immune responses, such as survival of Th17 cells and homeostasis of NK cells among others. Because of its impact in the immune system, we investigated the role of osteopontin in the homeostasis of IEL. In this study, we report that mice deficient in the expression of osteopontin exhibit reduced numbers of the IEL subpopulations TCRγδ+, TCRβ+CD4+, TCRβ+CD4+CD8α+, and TCRβ+CD8αα+ cells in comparison with wild-type mice. For some IEL subpopulations, the decrease in cell numbers could be attributed to apoptosis and reduced cell division. Moreover, we show in vitro that exogenous osteopontin stimulates the survival of murine IEL subpopulations and unfractionated IEL derived from human intestines, an effect mediated by CD44, a known osteopontin receptor. We also show that iCD8α IEL but not TCRγδ+ IEL, TCRβ+ IEL, or intestinal epithelial cells, can promote survival of different IEL populations via osteopontin, indicating an important role for iCD8α cells in the homeostasis of IEL.
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Affiliation(s)
- Ali Nazmi
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232
| | - Michael J Greer
- Department of Biomedical Informatics, Vanderbilt University, Nashville, TN 37232
| | - Kristen L Hoek
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232
| | - M Blanca Piazuelo
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232
| | - Joern-Hendrik Weitkamp
- Department of Pediatrics, Vanderbilt University Medical Center, Monroe Carell Jr. Children's Hospital, Nashville, TN 37232; and
| | - Danyvid Olivares-Villagómez
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232; .,Vanderbilt Institute for Infection, Immunology and Inflammation, Vanderbilt University Medical Center, Nashville, TN 37232
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17
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Pietrantonio F, Miceli R, Raimondi A, Kim YW, Kang WK, Langley RE, Choi YY, Kim KM, Nankivell MG, Morano F, Wotherspoon A, Valeri N, Kook MC, An JY, Grabsch HI, Fucà G, Noh SH, Sohn TS, Kim S, Di Bartolomeo M, Cunningham D, Lee J, Cheong JH, Smyth EC. Individual Patient Data Meta-Analysis of the Value of Microsatellite Instability As a Biomarker in Gastric Cancer. J Clin Oncol 2019; 37:3392-3400. [PMID: 31513484 DOI: 10.1200/jco.19.01124] [Citation(s) in RCA: 295] [Impact Index Per Article: 49.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/06/2019] [Indexed: 12/22/2022] Open
Abstract
PURPOSE In the CLASSIC and MAGIC trials, microsatellite instability (MSI)-high status was a favorable prognostic and potential negative predictive factor for neoadjuvant/adjuvant chemotherapy in resectable gastric cancer (GC). Given the low prevalence of MSI-high status in GC and its association with other positive prognostic variables, large data sets are needed to draw robust evidence of its prognostic/predictive value. PATIENTS AND METHODS We performed a multinational, individual-patient-data meta-analysis of the prognostic/predictive role of MSI in patients with resectable GC enrolled in the MAGIC, CLASSIC, ARTIST, and ITACA-S trials. Prognostic analyses used multivariable Cox models (MVM). The predictive role of MSI was assessed both in an all-comer population and in MAGIC and CLASSIC trials by MVM testing of the interaction of treatment (chemotherapy plus surgery v surgery) with MSI. RESULTS MSI status was available for 1,556 patients: 121 (7.8%) had MSI-high status; 576 were European, and 980 were Asian. In MSI-high versus MSI-low/microsatellite stable (MSS) comparisons, the 5-year disease-free survival (DFS) was 71.8% (95% CI, 63.8% to 80.7%) versus 52.3% (95% CI, 49.7% to 55.1%); the 5-year overall survival (OS) was 77.5% (95% CI, 70.0% to 85.8%) versus 59.3% (95% CI, 56.6% to 62.1%). In MVM, MSI was associated with longer DFS (hazard ratio [HR], 1.88; 95% CI, 1.28 to 2.76; P < .001) and OS (HR, 1.78; 95% CI, 1.17 to 2.73; P = .008), as were pT, pN, ethnicity, and treatment. Patients with MSI-low/MSS GC benefitted from chemotherapy plus surgery: the 5-year DFS compared with surgery only was 57% versus 41% (HR, 0.65; 95% CI, 0.53 to 0.79), and the 5-year OS was 62% versus 53% (HR, 0.75; 95% CI, 0.60 to 0.94). Conversely, those with MSI-high GC did not: the 5-year DFS was 70% versus 77% (HR, 1.27; 95% CI, 0.53 to 3.04), and the 5-year OS was 75% versus 83% (HR, 1.50; 95% CI, 0.55 to 4.12). CONCLUSION In patients with resectable primary GC, MSI is a robust prognostic marker that should be adopted as a stratification factor by clinical trials. Chemotherapy omission and/or immune checkpoint blockade should be investigated prospectively in MSI-high GCs according to clinically and pathologically defined risk of relapse.
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Affiliation(s)
- Filippo Pietrantonio
- Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
- University of Milan, Milan, Italy
| | - Rosalba Miceli
- Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | | | | | - Won Ki Kang
- Samsung Medical Center Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Ruth E Langley
- The Medical Research Council Clinical Trials Unit at University College London, London, United Kingdom
| | | | - Kyoung-Mee Kim
- Samsung Medical Center Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Matthew Guy Nankivell
- The Medical Research Council Clinical Trials Unit at University College London, London, United Kingdom
| | - Federica Morano
- Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | | | - Nicola Valeri
- The Institute of Cancer Research, London, United Kingdom
- GROW School for Oncology and Developmental Biology, Maastricht University Medical Center+, Maastricht, The Netherlands
| | | | - Ji Yeong An
- Samsung Medical Center Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Heike I Grabsch
- Leeds Institute for Medical Research at St James's, University of Leeds, Leeds, United Kingdom
- Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
| | - Giovanni Fucà
- Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | | | - Tae Sung Sohn
- Samsung Medical Center Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Sung Kim
- Samsung Medical Center Sungkyunkwan University School of Medicine, Seoul, Korea
| | | | | | - Jeeyun Lee
- Samsung Medical Center Sungkyunkwan University School of Medicine, Seoul, Korea
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18
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Zhang W, Huang L, Lu X, Wang K, Ning X, Liu Z. Upregulated expression of MNX1-AS1 long noncoding RNA predicts poor prognosis in gastric cancer. Bosn J Basic Med Sci 2019; 19:164-171. [PMID: 30821221 DOI: 10.17305/bjbms.2019.3713] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2018] [Accepted: 09/30/2018] [Indexed: 12/16/2022] Open
Abstract
As important regulators of gene expression long noncoding RNAs (lncRNAs) are implicated in various physiological and pathological processes, including cancer. An oncogenic role of MNX1 antisense RNA 1 (MNX1-AS1) lncRNA has been suggested in cervical cancer and glioblastoma. In this study, we investigated the clinicopathological significance and biological function of MNX1-AS1 in gastric cancer (GC). The expression of MNX1-AS1 was analyzed by qRT-PCR in 96 GC and adjacent non-tumor tissues in relation to clinicopathological features and overall survival (OS) of patients, and in five human GC cell lines compared to a normal gastric epithelial cell line. Loss-of-function experiments using small interfering RNA (siRNA) targeting MNX1-AS1 (si-MNX1-AS1) were carried out in AGS and MGC-803 GC cell lines. Cell proliferation (CCK-8 assay), migration (Transwell) and invasion (Transwell Matrigel), and protein expression of proliferating cell nuclear antigen (PCNA), E-cadherin, N-cadherin, vimentin and matrix metallopeptidase 9 (MMP-9) were analyzed in transfected GC cells. Expression of MNX1-AS1 was significantly higher in GC vs. adjacent non-tumor tissues. Higher MNX1-AS1 expression was significantly associated with tumor size, TNM stage and lymph node metastasis. Kaplan-Meier analysis showed that GC patients with higher MNX1-AS1 expression had worse OS compared to patients with lower MNX1-AS1 expression. Multivariate analysis showed that MNX1-AS1 is an independent poor prognostic factor in GC. Knockdown of MNX1-AS1 significantly inhibited proliferation, migration and invasion of AGS and MGC-803 cells, and resulted in increased E-cadherin and decreased PCNA, N-cadherin, vimentin and MMP-9 expression. Taken together, these results suggest that MNX1-AS1 has an oncogenic function in GC and potential as a molecular target in GC therapy.
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Affiliation(s)
- Wei Zhang
- Department of Gastrointestinal Surgery, Affiliated Hospital of Jining Medical University, Jining, Shandong Province, China.
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19
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van den Ende T, Ter Veer E, Mali RMA, van Berge Henegouwen MI, Hulshof MCCM, van Oijen MGH, van Laarhoven HWM. Prognostic and Predictive Factors for the Curative Treatment of Esophageal and Gastric Cancer in Randomized Controlled Trials: A Systematic Review and Meta-Analysis. Cancers (Basel) 2019; 11:E530. [PMID: 31013858 PMCID: PMC6521055 DOI: 10.3390/cancers11040530] [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: 02/02/2019] [Revised: 04/05/2019] [Accepted: 04/09/2019] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND An overview of promising prognostic variables and predictive subgroups concerning the curative treatment of esophageal and gastric cancer from randomized controlled trials (RCTs) is lacking. Therefore, we conducted a systematic review and meta-analysis. METHODS PubMed, EMBASE, CENTRAL, and ASCO/ESMO conferences were searched up to March 2019 for RCTs on the curative treatment of esophageal or gastric cancer with data on prognostic and/or predictive factors for overall survival. Prognostic factors were deemed potentially clinically relevant according to the following criteria; (1) statistically significant (p < 0.05) in a multivariate analysis, (2) reported in at least 250 patients, and (3) p < 0.05, in ≥ 33% of the total number of patients in RCTs reporting this factor. Predictive factors were potentially clinically-relevant if (1) the p-value for interaction between subgroups was <0.20 and (2) the hazard ratio in one of the subgroups was significant (p < 0.05). RESULTS For gastric cancer, 39 RCTs were identified (n = 13,530 patients) and, for esophageal cancer, 33 RCTs were identified (n = 8618 patients). In total, we identified 23 potentially clinically relevant prognostic factors for gastric cancer and 16 for esophageal cancer. There were 15 potentially clinically relevant predictive factors for gastric cancer and 10 for esophageal cancer. CONCLUSION The identified prognostic and predictive factors can be included and analyzed in future RCTs and be of guidance for nomograms. Further validation should be performed in large patient cohorts.
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Affiliation(s)
- Tom van den Ende
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Centers, (UMC) location AMC, University of Amsterdam, 1105 AZ, Amsterdam, The Netherlands.
| | - Emil Ter Veer
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Centers, (UMC) location AMC, University of Amsterdam, 1105 AZ, Amsterdam, The Netherlands.
| | - Rosa M A Mali
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Centers, (UMC) location AMC, University of Amsterdam, 1105 AZ, Amsterdam, The Netherlands.
| | - Mark I van Berge Henegouwen
- Department of Surgery, Cancer Center Amsterdam, Amsterdam University Medical Centers, (UMC) location AMC, University of Amsterdam, 1105 AZ, Amsterdam, The Netherlands.
| | - Maarten C C M Hulshof
- Department of Radiotherapy, Cancer Center Amsterdam, Amsterdam University Medical Centers (UMC), location AMC, University of Amsterdam, 1105 AZ, Amsterdam, The Netherlands.
| | - Martijn G H van Oijen
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Centers, (UMC) location AMC, University of Amsterdam, 1105 AZ, Amsterdam, The Netherlands.
| | - Hanneke W M van Laarhoven
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Centers, (UMC) location AMC, University of Amsterdam, 1105 AZ, Amsterdam, The Netherlands.
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20
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Ke B, Guo XF, Li N, Wu LL, Li B, Zhang RP, Liang H. Clinical significance of Stathmin1 expression and epithelial-mesenchymal transition in curatively resected gastric cancer. Mol Clin Oncol 2018; 10:214-222. [PMID: 30680197 PMCID: PMC6327211 DOI: 10.3892/mco.2018.1774] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2018] [Accepted: 11/15/2018] [Indexed: 02/06/2023] Open
Abstract
In our previous study, it was demonstrated that the Stathmin1 (STMN1) is overexpressed in gastric cancer (GC) and that its high expression level is associated with tumor invasion and metastasis. Epithelial-mesenchymal transition (EMT) has also been shown to be critically involved in GC invasion and metastasis. Certain studies have indicated that STMN1 may serve an important role in the EMT process. However, the association between STMN1 expression and EMT-associated markers, as well as clinicopathological characteristics of patients with GC, remains unclear. The aim of the present study was to investigate the clinicopathological significance and prognostic value of STMN1 and EMT-associated markers in GC. The expression of STMN1 and the EMT-associated proteins E-cadherin (E-Cad) and vimentin (VIM) were analyzed by immunohistochemistry in GC and adjacent non-tumorous tissues. Associations between the expression of these markers and clinicopathological parameters were analyzed. The association between STMN1 expression and EMT-associated markers was investigated in the GC cell lines BGC-803 and SGC-7901. The results revealed that STMN1 was expressed in 63.5% of the 167 GC tissues, which was significantly higher than the percentage observed in the adjacent non-tumorous tissues (P=0.003). The STMN1 expression was demonstrated to be positively associated with the VIM levels (P=0.001) and negatively associated with the E-Cad levels (P=0.022) in GC tissues. The STMN1 expression was associated with Lauren's Classification, invasion depth, lymph node metastasis and pathological Tumor-Node-Metastasis (pTNM) stage (P<0.05). In the univariate analyses, the high E-Cad expression was a positive prognostic indicator for overall survival, whereas the high STMN1 and VIM expression was a negative indicator. COX multiple regression analysis demonstrated that the pTNM stage [hazard ratio (HR) 1.912, 95% confidence interval (CI): 1.282–2.851, P=0.001] and E-Cad expression (HR 0.403, 95% CI: 0.249–0.650, P=0.000) were independent prognostic factors. It was also revealed that the expression level of E-Cad decreased, while the expression level of VIM increased by depleting STMN1 levels in GC cells. The present results suggest that the aberrant expression of STMN1 may promote tumor progression through EMT in GC.
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Affiliation(s)
- Bin Ke
- Department of Gastric Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, P.R. China
| | - Xiao-Fan Guo
- Department of Gastric Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, P.R. China
| | - Ning Li
- Department of Gastric Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, P.R. China
| | - Liang-Liang Wu
- Department of Gastric Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, P.R. China
| | - Bin Li
- Department of Gastric Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, P.R. China
| | - Ru-Peng Zhang
- Department of Gastric Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, P.R. China
| | - Han Liang
- Department of Gastric Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, P.R. China
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21
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Icer MA, Gezmen-Karadag M. The multiple functions and mechanisms of osteopontin. Clin Biochem 2018; 59:17-24. [PMID: 30003880 DOI: 10.1016/j.clinbiochem.2018.07.003] [Citation(s) in RCA: 381] [Impact Index Per Article: 54.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Revised: 07/03/2018] [Accepted: 07/08/2018] [Indexed: 12/12/2022]
Abstract
Osteopontin (OPN) is a highly phosphorylated glycophosphoprotein having acidic characteristics and rich in aspartic acid. OPN, a multifunctional protein, has important functions on cardiovascular diseases, cancer, diabetes and kidney stone diseases and in the process of inflammation, biomineralization, cell viability and wound healing. Osteopontin acts on organisms by playing a key role in secretion levels of interleukin-10 (IL-10), interleukin-12 (IL-12), interleukin-3 (IL-3), interferon-γ (IFN-γ), integrin αvB3, nuclear factor kappa B (NF-kB), macrophage and T cells, regulating the osteoclast function and affecting CD44 receptors. The aim of the present review is to address majority of different functions of OPN protein which are known, suspected or suggested through the data obtained about this protein yet.
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Affiliation(s)
- Mehmet Arif Icer
- Gazi University, Faculty of Health Sciences, Nutrition and Dietetics Department, 06500 Beşevler, Ankara, Turkey.
| | - Makbule Gezmen-Karadag
- Gazi University, Faculty of Health Sciences, Nutrition and Dietetics Department, 06500 Beşevler, Ankara, Turkey.
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22
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Giampieri R, Del Prete M, Cantini L, Baleani MG, Bittoni A, Maccaroni E, Berardi R. Optimal management of resected gastric cancer. Cancer Manag Res 2018; 10:1605-1618. [PMID: 29950898 PMCID: PMC6016582 DOI: 10.2147/cmar.s151552] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Although advances in medical treatment for gastric cancer (GC) have been made, surgery remains the mainstay of cure for patients with localized disease. Improvement in surgical modalities leads to increased chance of cure for resected patients, but a non-negligible number of patients eventually relapse. On this basis, it has been hypothesized that the addition of complementary systemic or local treatments (such as chemotherapy and radiotherapy) could help in improving patients' survival by reducing the risk of recurrence. Several studies have tried to identify the best approach in localized GC: some of them have assessed the role of perioperative chemotherapy [CT] with different drug combinations, while others have focused on the benefit obtained by addition of radiotherapy, whose role is still under investigation. In particular, the role of chemoradiotherapy, both in adjuvant and neoadjuvant settings, is still uncertain. In the last few years, several clinicopathological and molecular factors have been investigated and identified as potential prognostic markers in GC. Many of these factors could have influenced the outcome of patients receiving combined treatments in the abovementioned studies. Patients have not been generally distinguished by the site of disease (esophageal, gastric and junctional cancers) and surgical approach, making data difficult to be interpreted. The purpose of this review was to shed light on these highly controversial topics.
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Affiliation(s)
- Riccardo Giampieri
- Oncology Clinic, AOU Ospedali Riuniti, Università Politecnica delle Marche, Ancona, Italy
| | - Michela Del Prete
- Oncology Clinic, AOU Ospedali Riuniti, Università Politecnica delle Marche, Ancona, Italy
| | - Luca Cantini
- Oncology Clinic, AOU Ospedali Riuniti, Università Politecnica delle Marche, Ancona, Italy
| | - Maria Giuditta Baleani
- Oncology Clinic, AOU Ospedali Riuniti, Università Politecnica delle Marche, Ancona, Italy
| | - Alessandro Bittoni
- Oncology Clinic, AOU Ospedali Riuniti, Università Politecnica delle Marche, Ancona, Italy
| | - Elena Maccaroni
- Oncology Clinic, AOU Ospedali Riuniti, Università Politecnica delle Marche, Ancona, Italy
| | - Rossana Berardi
- Oncology Clinic, AOU Ospedali Riuniti, Università Politecnica delle Marche, Ancona, Italy
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23
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Wei R, Wong JPC, Lyu P, Xi X, Tong O, Zhang SD, Yuen HF, Shirasawa S, Kwok HF. In vitro and clinical data analysis of Osteopontin as a prognostic indicator in colorectal cancer. J Cell Mol Med 2018; 22:4097-4105. [PMID: 29851214 PMCID: PMC6111822 DOI: 10.1111/jcmm.13686] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2018] [Accepted: 04/21/2018] [Indexed: 12/25/2022] Open
Abstract
Osteopontin (OPN) has been shown to promote colorectal cancer (CRC) progression; however, the mechanism of OPN-induced CRC progression is largely unknown. In this study, we found that OPN overexpression led to enhanced anchorage-independent growth, cell migration and invasion in KRAS gene mutant cells but to a lesser extent in KRAS wild-type cells. OPN overexpression also induced PI3K signalling, expression of Snail and Matrix metallopeptidase 9 (MMP9), and suppressed the expression of E-cadherin in KRAS mutant cells. In human CRC specimens, a high-level expression of OPN significantly predicted poorer survival in CRC patients and OPN expression was positively correlated with MMP9 expression, and negatively correlated with E-cadherin expression. Furthermore, we have found that 15 genes were co-upregulated in OPN highly expression CRC and a list of candidate drugs that may have potential to reverse the secreted phosphoprotein 1 (SPP1) gene signature by connectivity mapping. In summary, OPN is a potential prognostic indicator and therapeutic target for colon cancer.
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Affiliation(s)
- Ran Wei
- Faculty of Health Sciences, University of Macau, Taipa, Macau
| | | | - Peng Lyu
- Faculty of Health Sciences, University of Macau, Taipa, Macau
| | - Xinping Xi
- Faculty of Health Sciences, University of Macau, Taipa, Macau
| | - Olivia Tong
- Faculty of Health Sciences, University of Macau, Taipa, Macau
| | - Shu-Dong Zhang
- Northern Ireland Centre for Stratified Medicine, Biomedical Sciences Research Institute, University of Ulster, Londonderry, UK
| | - Hiu Fung Yuen
- Institute of Molecular and Cell Biology, A*STAR, Singapore City, Singapore
| | - Senji Shirasawa
- Department of Cell Biology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
| | - Hang Fai Kwok
- Faculty of Health Sciences, University of Macau, Taipa, Macau
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24
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Hua G, Yanjiao H, Qian L, Jichao W, Yazhuo Z. Detection of circulating tumor cells in patients with pituitary tumors. BMC Cancer 2018; 18:336. [PMID: 29587659 PMCID: PMC5870253 DOI: 10.1186/s12885-018-4162-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2016] [Accepted: 02/21/2018] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Circulating tumor cells (CTCs) are tumor cells that have shed from a primary tumor and circulate in the peripheral blood. Recent experimental and clinical studies show that CTCs can be detected in early-stage disease. CASE PRESENTATION We report three cases of pituitary adenoma (PA) in which tumor cells with particles were detected in the interstitial vascular compartment by transmission electron microscopy. Tumors were completely resected. Immunohistochemical analysis showed a β-catenin score of 10.5 ± 1.5 in the three cases with CTCs compared with 2.4 ± 0.5 in 24 control adenomas. The Ki-67 labeling index was 2.1 ± 0.7 in CTCs vs. 0.2 ± 0.3 in control cases (p = 0.043), and the p53 score was 4.33 ± 1.3 vs. 0.31 ± 0.17 (p = 0.000). The E-cadherin score did not differ significantly between the two groups. CONCLUSIONS CTCs can be detected in benign tumors such as PAs and not only in late-stage malignant tumors with apparent distant metastases. The present findings suggest that pituitary carcinomas develop from adenomas.
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Affiliation(s)
- Gao Hua
- Beijing Neurosurgical Insititute, Capital Medical University, Tiantan xili 6#, Beijing, 100050, China.,Key laboratory of central nervous system injury research, Tiantan xili 6#, Beijing, 100050, China.,Center of Brain Tumor, Beijing Institute for Brain Disorders, Tiantan xili 6#, Beijing, 100050, China.,China National Clinical Research Center for Neurological Diseases, Tiantan xili 6#, Beijing, 100050, China
| | - He Yanjiao
- Beijing Neurosurgical Insititute, Capital Medical University, Tiantan xili 6#, Beijing, 100050, China
| | - Liu Qian
- Beijing Neurosurgical Insititute, Capital Medical University, Tiantan xili 6#, Beijing, 100050, China.,Center of Brain Tumor, Beijing Institute for Brain Disorders, Tiantan xili 6#, Beijing, 100050, China
| | - Wang Jichao
- Department of Neurosurgery, Xinjiang Uygur Autonomous Region People's Hospital, Xinjiang, 830000, China
| | - Zhang Yazhuo
- Beijing Neurosurgical Insititute, Capital Medical University, Tiantan xili 6#, Beijing, 100050, China. .,Key laboratory of central nervous system injury research, Tiantan xili 6#, Beijing, 100050, China. .,Center of Brain Tumor, Beijing Institute for Brain Disorders, Tiantan xili 6#, Beijing, 100050, China. .,China National Clinical Research Center for Neurological Diseases, Tiantan xili 6#, Beijing, 100050, China.
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25
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Recombinant human bone morphogenetic protein-2 inhibits gastric cancer cell proliferation by inactivating Wnt signaling pathway via c-Myc with aurora kinases. Oncotarget 2018; 7:73473-73485. [PMID: 27636990 PMCID: PMC5341992 DOI: 10.18632/oncotarget.11969] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2016] [Accepted: 09/02/2016] [Indexed: 01/12/2023] Open
Abstract
The detailed molecular mechanisms and safety issues of recombinant human bone morphogenetic protein-2 (rhBMP-2) usage in bone graft substitution remain poorly understood. To investigate the molecular mechanisms underlying the function of rhBMP-2 in gastric cancer cells, we used microarrays to determine the gene expression patterns related to the effects of rhBMP-2. Based on a gene ontology analysis, several genes were upregulated during the regulation of the cell cycle and BMP signaling pathway. MYC was found to be significantly decreased along with its downstream target genes, the aurora kinases (AURKs), by rhBMP-2 in the network analysis. We further confirmed this finding with western blot data that rhBMP-2 inhibited c-Myc, AURKs, and β-catenin in SNU484 and SNU638 cells. An AURK inhibitor significantly decreased c-Myc expression in gastric cancer cells. Combination treatment with rhBMP-2 and AURK inhibitor resulted in significantly decreased c-Myc expression compared with gastric cancer cells treated with an rhBMP-2 or AURK inhibitor, respectively. Similar effects for decreased c-Myc expression were observed when we silenced β-catenin in gastric cancer cells. These results indicate that rhBMP-2 attenuated the growth of gastric cancer cells via the inactivation of β-catenin via c-Myc and AURKs. Therefore, our findings suggest that rhBMP-2 could be safely used with patients who undergo gastric or gastroesophageal cancer surgery.
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26
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Gu X, Gao XS, Ma M, Qin S, Qi X, Li X, Sun S, Yu H, Wang W, Zhou D. Prognostic significance of osteopontin expression in gastric cancer: a meta-analysis. Oncotarget 2018; 7:69666-69673. [PMID: 27626167 PMCID: PMC5342506 DOI: 10.18632/oncotarget.11936] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2016] [Accepted: 09/02/2016] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Accumulated studies have exploited the association between osteopontin (OPN) expression and survival of patients with gastric cancer (GC), however, the results were controversial. Thus, we performed a meta-analysis, aiming to investigate the prognostic role of OPN for GC patients and to explore the association between OPN and clinicalpathological features of GC. RESULTS A total of ten studies involving 1775 patients were included in final meta-analysis. Of the included studies, nine were conducted on Asian patients and one was performed on Caucasian patients. Regarding OPN detection, immunohistochemistry (IHC) was used on tissue specimens in eight studies and enzyme linked immunosorbent assay (ELISA) was used on plasma specimens in two studies. The pooled data showed that high OPN expression was correlated with poor OS (HR = 1.59, 95% CI: 1.15-2.22, p = 0.006). Subgroup analyses demonstrated that OPN had enhanced prognostic value for Asian patients (HR = 1.64, 95% CI = 1.11-2.41, p = 0.012) and for patients receiving surgical resection (HR = 1.6, 95% CI = 1.04-2.48, p = 0.034). In addition, the results also showed that elevated OPN expression was associated with lymph node metastasis, TNM stage, depth of invasion, tumor size and distant metastasis in GC. METHODS Relevant studies were retrieved through PubMed, Embase and Web of Science. Combined hazard ratio (HR) and 95% confidence interval (CI) were calculated to assess the association between OPN and overall survival (OS). Subgroup analyses and publication bias were also conducted. CONCLUSIONS OPN overexpression was correlated with poor OS and clinical features reflecting high aggressiveness in patients with GC. OPN was a promising prognostic biomarker for GC.
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Affiliation(s)
- Xiaobin Gu
- Department of Radiation Oncology, Peking University First Hospital, Peking University, Beijing, China
| | - Xian-Shu Gao
- Department of Radiation Oncology, Peking University First Hospital, Peking University, Beijing, China
| | - Mingwei Ma
- Department of Radiation Oncology, Peking University First Hospital, Peking University, Beijing, China
| | - Shangbin Qin
- Department of Radiation Oncology, Peking University First Hospital, Peking University, Beijing, China
| | - Xin Qi
- Department of Radiation Oncology, Peking University First Hospital, Peking University, Beijing, China
| | - Xiaoying Li
- Department of Radiation Oncology, Peking University First Hospital, Peking University, Beijing, China
| | - Shaoqian Sun
- Department of Radiation Oncology, Peking University First Hospital, Peking University, Beijing, China
| | - Hao Yu
- Department of Radiation Oncology, Peking University First Hospital, Peking University, Beijing, China
| | - Wen Wang
- Department of Radiation Oncology, Peking University First Hospital, Peking University, Beijing, China
| | - Dong Zhou
- Department of Radiation Oncology, Peking University First Hospital, Peking University, Beijing, China
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Wu H, Zhang H, Hu LY, Zhang TY, Zheng YJ, Shen F, Yang T. Is osteopontin a promising prognostic biomarker for cholangiocarcinoma? J Hepatol 2017; 68:S0168-8278(17)32269-9. [PMID: 28870677 DOI: 10.1016/j.jhep.2017.08.029] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2017] [Accepted: 08/11/2017] [Indexed: 12/12/2022]
Affiliation(s)
- Han Wu
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China
| | - Han Zhang
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China
| | - Lun-Yang Hu
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China; Department of Clinical Medicine, Second Military Medical University, Shanghai 200433, China
| | - Tian-Yi Zhang
- Department of Health Statistics, Second Military Medical University, Shanghai 200433, China
| | - Yi-Jie Zheng
- Medical Scientific Affairs, Abbott Diagnostics, Shanghai 200003, China
| | - Feng Shen
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China
| | - Tian Yang
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China.
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Petrelli F, Berenato R, Turati L, Mennitto A, Steccanella F, Caporale M, Dallera P, de Braud F, Pezzica E, Di Bartolomeo M, Sgroi G, Mazzaferro V, Pietrantonio F, Barni S. Prognostic value of diffuse versus intestinal histotype in patients with gastric cancer: a systematic review and meta-analysis. J Gastrointest Oncol 2017; 8:148-163. [PMID: 28280619 DOI: 10.21037/jgo.2017.01.10] [Citation(s) in RCA: 79] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND There are two distinct types of gastric carcinoma (GC), intestinal, more frequently sporadic and linked to environmental factors, and diffuse (undifferentiated) that is highly metastatic and characterized by rapid disease progression and a poor prognosis. However, there are many conflicting data in the literature concerning the association between histology and prognosis in GC. This meta-analysis was performed to provide demonstration if histology according to Lauren classification is associated with different prognosis in patients with GC. METHODS We searched PubMed, the Cochrane Library, SCOPUS, Web of Science, CINAHL, and EMBASE for all eligible studies. The combined hazard ratios (HRs) and their corresponding 95% confidence intervals (CIs) in terms of overall survival (OS) were evaluated. RESULTS A total of 73 published studies including 61,468 patients with GC were included in this meta-analysis. Our analysis indicates that GC patients with diffuse-type histology have a worst prognosis than those with intestinal subgroup in all studies (HR 1.23; 95% CI, 1.17-1.29; P<0.0001), in both loco-regional confined (HR 1.21; 95% CI, 1.12-1.30; P<0.0001) and advanced disease (HR 1.25; 95% CI, 1.046-1.50; P=0.014), in Asiatic (HR 1.2; 95% CI, 1.14-1.27; P<0.0001) and Western patients (HR 1.3; 95% CI, 1.19-1.41; P<0.0001), and in those not exposed (HR 1.15; 95% CI, 1.07-1.24; P<0.0001) or exposed (HR 1.27; 95% CI, 1.17-1.37; P<0.0001) to (neo)adjuvant therapy. CONCLUSIONS Our results indicated that histology might be a useful prognostic marker for both early and advanced GC patients, with intestinal-type associated with a better outcome. This information could be used for stratification purpose in future clinical trials.
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Affiliation(s)
- Fausto Petrelli
- Medical Oncology Unit, Oncology Department, ASST Bergamo Ovest, Treviglio (BG), Italy
| | - Rosa Berenato
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Luca Turati
- Surgical Oncology Unit, Surgery Department, ASST Bergamo Ovest, Treviglio (BG), Italy
| | - Alessia Mennitto
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Francesca Steccanella
- Surgical Oncology Unit, Surgery Department, ASST Bergamo Ovest, Treviglio (BG), Italy
| | - Marta Caporale
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Pierpaolo Dallera
- Surgical Oncology Unit, Surgery Department, ASST Bergamo Ovest, Treviglio (BG), Italy
| | - Filippo de Braud
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Ezio Pezzica
- Pathology Unit, Oncology Department, ASST Bergamo Ovest, Treviglio (BG), Italy
| | - Maria Di Bartolomeo
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Giovanni Sgroi
- Surgical Oncology Unit, Surgery Department, ASST Bergamo Ovest, Treviglio (BG), Italy
| | - Vincenzo Mazzaferro
- Hepatobiliopancreatic Surgery Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Filippo Pietrantonio
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Sandro Barni
- Medical Oncology Unit, Oncology Department, ASST Bergamo Ovest, Treviglio (BG), Italy
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Ishiguro H, Wakasugi T, Terashita Y, Sakamoto N, Tanaka T, Mizoguchi K, Sagawa H, Okubo T, Takeyama H. Decreased expression of CDH1 or CTNNB1 affects poor prognosis of patients with esophageal cancer. World J Surg Oncol 2016; 14:240. [PMID: 27600761 PMCID: PMC5012100 DOI: 10.1186/s12957-016-0956-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2016] [Accepted: 07/20/2016] [Indexed: 12/13/2022] Open
Abstract
Background E-cadherin/CDH1 is one of the proteins involved in cell adhesion, and it is known that decreased expression of E-cadherin induces lymph node metastasis in esophageal cancer. Beta catenin/CTNNB1, which is an important component of the Wnt signaling pathway, binds to E-cadherin at the cell membrane, where the complex of these two proteins functions in the stabilization of cell adhesion. However, its role in the pathogenesis of esophageal cancer is still unknown. Methods This study included 86 patients with esophageal cancer who underwent surgery between 1998 and 2007. The expression of the E-cadherin/CDH1 gene product (E-cadherin/CDH1) and that of the beta catenin/CTNNB1 protein in the cell membrane were analyzed by immunohistochemistry. We examined the correlations among CDH1 or CTNNB1 expression, clinicopathological factors, and the prognosis of patients with ESCC. Results CDH1 and CTNNB1 were expressed in 52.3 % (45/86) and 36.0 % (31/86) of tumor samples, respectively. Both CDH1 and CTNNB1 were co-expressed in 22.1 % (19/86) of esophageal cancer tissues. CDH1 expression correlated with the p-stage (stages I–II vs stages III–IV, p = 0.032), T factor (T1–2 vs T3–4, p = 0.0088), and lymphatic invasion (p = 0.019). However, CDH1 expression did not correlate with the N factor or the blood vessel invasion. CTNNB1 expression correlated with the T factor (T1–2 vs T3–4, p = 0.0015), p-stage (stages I–II vs stages III–IV, p = 0.030), and lymphatic invasion (p = 0.007). The CDH1(+)/CTNNB1(+) phenotype was inversely correlated with the T factor, N factor, p-stage, lymphatic invasion, and blood vessel invasion. Furthermore, patients whose tumors were double-positive for CDH1 and CTNNB1 had a significantly higher survival rate than those whose tumors were negative for CDH1 or CTNNB1 (log-rank test, p = 0.0192). The T factor and N factor had a strong negative correlation with double-positive tumors. These were both independent prognostic factors, as was the double-positive phenotype. A univariate analysis indicated that the T factor, the N factor, and CDH1 and CTNNB1 co-expression were significant variables that predicted survival (hazard ratio, 2.387; 95 % confidence interval, 1.115–5.102; p = 0.025). Conclusions Decreased expression of CDH1 or CTNNB1 in the cell membranes of cancer cells is associated with poor survival of patients with esophageal cancer.
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Affiliation(s)
- Hideyuki Ishiguro
- Gastroenterological Surgery, Nagoya City University Graduate School of Medical Science, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan.
| | - Takehiro Wakasugi
- Gastroenterological Surgery, Nagoya City University Graduate School of Medical Science, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan
| | - Yukio Terashita
- Gastroenterological Surgery, Nagoya City University Graduate School of Medical Science, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan
| | - Nobuhiro Sakamoto
- Gastroenterological Surgery, Nagoya City University Graduate School of Medical Science, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan
| | - Tatsuya Tanaka
- Gastroenterological Surgery, Nagoya City University Graduate School of Medical Science, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan
| | - Koji Mizoguchi
- Gastroenterological Surgery, Nagoya City University Graduate School of Medical Science, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan
| | - Hiroyuki Sagawa
- Gastroenterological Surgery, Nagoya City University Graduate School of Medical Science, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan
| | - Tomotaka Okubo
- Gastroenterological Surgery, Nagoya City University Graduate School of Medical Science, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan
| | - Hiromitsu Takeyama
- Gastroenterological Surgery, Nagoya City University Graduate School of Medical Science, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan
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Pu J, Xu L, Yin X, Zhang B. Intracranial hypertension as the primary symptom of gastric signet-ring cell carcinoma: A case report and literature review. Medicine (Baltimore) 2016; 95:e4687. [PMID: 27583897 PMCID: PMC5008581 DOI: 10.1097/md.0000000000004687] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Intracranial hypertension (IH) is a neurological disorder characterized by increased intracranial pressure. It is a poorly understood syndrome that most commonly manifests nonspecific symptoms such as stroke-like headache, vision changes, nausea, vomiting, and papilledema. IH has been reported in young cancer patients but never in association with gastric signet-ring cell carcinoma. METHODS Here, we discuss the case of an 18-year-old girl with gastric signet-ring cell carcinoma in which IH was the primary symptom accompanied by the even rarer symptom of cutaneous metastases. We also present a review of the relevant literature. The patient experienced frequent headaches, vomiting, and blurred vision but showed no abnormal findings on cranial imaging studies. Further examination showed multiple skin nodules on the abdomen. Then pathological and immunohistochemical examination of gastroscopic specimens and the biopsied subcutaneous nodules were done. RESULTS Pathological and immunohistochemical examination of gastroscopic specimens and the biopsied subcutaneous nodules confirmed gastric signet-ring cell carcinoma with skin metastases. CONCLUSION To our knowledge, this is the first reported case of gastric signet-ring cell carcinoma primarily presenting IH and accompanied by subcutaneous metastases. This case emphasizes the importance of excluding malignancy from the differential diagnosis of IH.
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Affiliation(s)
| | | | | | - Baorong Zhang
- Department of Neurology, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
- Correspondence: Baorong Zhang, Department of Neurology, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, People's Republic of China (e-mail: )
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31
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Zhong J, Chen Y, Wang LJ. Emerging molecular basis of hematogenous metastasis in gastric cancer. World J Gastroenterol 2016; 22:2434-2440. [PMID: 26937132 PMCID: PMC4768190 DOI: 10.3748/wjg.v22.i8.2434] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Revised: 10/29/2015] [Accepted: 11/19/2015] [Indexed: 02/06/2023] Open
Abstract
Lymphatic metastasis is commonly observed in gastric cancer (GC), but hematogenous metastasis is more likely responsible for the cancer-related mortality. Since Stephen Paget first introduced the “seed and soil hypothesis” a century ago, growing evidence recognizes that numerous essential secreted factors and signaling pathway effectors participate in the pre-metastatic niche formation and distant organ metastasis. The cross-talk between GC cells and surrounding microenvironment may consist of a series of interrelated steps, including epithelial mesenchymal transition, intravasation into blood vessels, circulating tumor cell translocation, and secondary organ metastasis. Secreted factors including vascular endothelial growth factor (VEGF), matrix metalloproteinases and cancer-derived extracellular vesicles, especially exosomes, are essential in formation of premetastatic niche. Circulating tumor cells and microRNAs represent as ‘‘metastatic intermediates’’ between primary tumors and sites of dissemination. Many biomarkers have been identified as novel metastatic markers and prognostic effectors. In addition, molecular therapy has been designed to target biomarkers such as growth factors (human epidermal growth factor receptor 2, VEGF) and chemokines, although they have not clearly proven to be effective in inhibiting GC metastasis in clinical trials. In this review, we will systematically discuss the emerging molecules and their microenvironment in hematogenous metastasis of GC, which may help us to find new therapeutic strategies in the future.
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Zheng Y, Li YF, Wang W, Chen YM, Wang DD, Zhao JJ, Pan QZ, Jiang SS, Zhang XF, Yuan SQ, Qiu HB, Huang CY, Zhao BW, Zhou ZW, Xia JC. High expression level of T-box transcription factor 5 predicts unfavorable survival in stage I and II gastric adenocarcinoma. Oncol Lett 2015; 10:2021-2026. [PMID: 26622790 PMCID: PMC4579827 DOI: 10.3892/ol.2015.3515] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2014] [Accepted: 03/18/2015] [Indexed: 12/22/2022] Open
Abstract
The expression of T-box transcription factor 5 (TBX5) has previously been observed in human cancer. The aim of the present study was to investigate TBX5 expression and its potential clinical significance in gastric cancer (GC). Using reverse transcription-quantitative polymerase chain reaction, the TBX5 mRNA expression levels in 30 pairs of surgically resected healthy gastric tissues and early stage (stages I and II) GC tissues were evaluated. The TBX5 mRNA expression levels were increased in GC stage I and II tumor tissues (P=0.01, n=30) compared with the matched adjacent non-tumor tissue. However, no significant difference was observed in TBX5 mRNA expression levels in matched adjacent non-tumor tissue compared with the tumor tissue from stage III and IV GC samples (P=0.318, n=30). Immunohistochemical analysis for TBX5 expression was performed on 161 paraffin-embedded stage I and II GC tissue blocks. Statistical analysis was performed to evaluate the associations between TBX5 expression, clinicopathological factors and prognosis. Patients with stage I and II GC and tumors with high TBX5 expression levels presented poor overall survival (OS) rate (P=0.024). The Cox proportional hazards model analysis demonstrated that TBX5 expression was an independent risk factor (P=0.017). The present study indicates that high expression of TBX5 is associated with unfavorable OS rates in patients with stage I and II GC. In conclusion, the expression of TBX5 may be a valuable biomarker for the selection of cases of high-risk stage I and II GC.
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Affiliation(s)
- Yan Zheng
- Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China ; Department of Thoracic Surgery, Henan Cancer Hospital, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan 450008, P.R. China
| | - Yuan-Fang Li
- Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China
| | - Wei Wang
- Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China
| | - Yong-Ming Chen
- Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China
| | - Dan-Dan Wang
- Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China ; National Laboratory for Bio-Drugs of Ministry of Health, Provincial Laboratory for Modern Medicine and Technology of Shandong, Research Center for Medicinal Biotechnology, Shandong Academy of Medical Sciences, Jinan, Shandong 250062, P.R. China
| | - Jing-Jing Zhao
- Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China
| | - Qiu-Zhong Pan
- Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China
| | - Shan-Shan Jiang
- Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China
| | - Xiao-Fei Zhang
- Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China
| | - Shu-Qiang Yuan
- Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China
| | - Hai-Bo Qiu
- Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China
| | - Chun-Yu Huang
- Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China
| | - Bai-Wei Zhao
- Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China
| | - Zhi-Wei Zhou
- Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China
| | - Jian-Chuan Xia
- Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China
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