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Wang K, Rao S, Wei X, Xie W, Hong Z, Cheng J, Chen X, Hou J, Zhuo H. Vesicle-mediated transport-related gene SEC23A promotes cell proliferation by regulating cell cycle leading to gastric cancer progression. Acta Biochim Biophys Sin (Shanghai) 2025. [PMID: 40400443 DOI: 10.3724/abbs.2025051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/23/2025] Open
Abstract
Gastric cancer (GC) is a highly prevalent and lethal gastrointestinal cancer. Dysregulation of vesicle-mediated transport-related genes (VMTRGs) is closely associated with tumorigenesis and disease progression. However, the prognostic value of VMTRGs in GC remains unclear. In this study, on the basis of our proteomics data and public databases, we identify differentially expressed VMTRGs in infiltrative-type GC with more metastases and recurrences identified by Ming's classification. Least absolute shrinkage and selection operator (LASSO) regression identifies 3 VMTRGs ( SEC23A, RAB31, and GABARAPL2) from 41 infiltrative-associated VMTRGs, based on which a risk model Vesicle-Infiltrative Lasso System (VILS) is constructed, and its effectiveness and potential importance are validated by immune microenvironment analysis and functional enrichment analysis. As an independent prognostic factor for GC, VILS, combined with other clinically independent prognostic factors to form a nomogram, is effective in predicting GC prognosis. The VILS high-risk group has higher M2 macrophage and cancer-associated fibroblast infiltration, and lower infiltration of Th1 cells and natural killer cells. SEC23A is highly expressed in GC tissues and cells. The importance of SEC23A in GC cells is evaluated by in vitro assays including colony formation assay and CCK-8 assay, and by in vivo assay using a subcutaneous xenograft mouse model. The results show that SEC23A promotes GC cell proliferation and tumor growth through regulation of the cell cycle in vitro and in vivo. VILS provides excellent prognostic prediction for GC patients and is correlated with antitumor immune cell infiltration. SEC23A, the dominant gene of VILS, is highly expressed in GC and promotes GC growth and malignant progression through various molecular mechanisms. Our study reveals the effect of SEC23A on the proliferation of gastric cancer cells for the first time. Therefore, SEC23A has the potential to be a new therapeutic target for the diagnosis and treatment of GC.
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Affiliation(s)
- Kang Wang
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361000, China
- Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen 361000, China
| | - Shihao Rao
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361000, China
- Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen 361000, China
| | - Xujin Wei
- Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen 361000, China
- The Graduate School of Fujian Medical University, Fuzhou 350000, China
| | - Wen Xie
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361000, China
- Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen 361000, China
| | - Zhijun Hong
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361000, China
- Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen 361000, China
| | - Jia Cheng
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361000, China
- Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen 361000, China
| | - Xin Chen
- Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen 361000, China
- The Graduate School of Fujian Medical University, Fuzhou 350000, China
| | - Jingjing Hou
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361000, China
- Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen 361000, China
| | - Huiqin Zhuo
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361000, China
- Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen 361000, China
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Goel A, Agrawal K, Mukherjee U, Singla V. Fundic gland adenocarcinoma. BMJ Case Rep 2024; 17:e261983. [PMID: 39631917 DOI: 10.1136/bcr-2024-261983] [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: 12/07/2024] Open
Abstract
Gastric malignancy is one of the most common malignancies diagnosed worldwide. Over the past many decades, extensive research has been made into the risk factors, pathogenesis and prognosis of gastric adenocarcinoma. However, gastric adenocarcinoma of the fundic gland (GA-FG) has been recently defined, and not much is known about its risk factors and pathogenesis. Since the first case, which was reported in 2007, only 195 cases have been described in the literature to date. The rarity of the lesion is the cause of unawareness of this entity among reporting pathologists, often leading to its misdiagnosis. Existing literature shows that the risk factors, pathogenesis and even the prognosis of GA-FG are remarkably different from gastric adenocarcinoma. Hence, early and correct diagnosis can have a significant impact on patient management and outcomes.
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Affiliation(s)
- Akash Goel
- Department of Gastroenterology, Hepatology and Endoscopy, Max Super Speciality Hospital Saket, New Delhi, Delhi, India
| | - Komal Agrawal
- Department of Histopathology, Max Super Speciality Hospital Saket, New Delhi, Delhi, India
| | - Urmi Mukherjee
- Department of Histopathology, Max Super Speciality Hospital, New Delhi, Delhi, India
| | - Vikas Singla
- Department of Gastroenterology, Hepatology and Endoscopy, Max Super Speciality Hospital Saket, New Delhi, Delhi, India
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Désilets A, Elkhoury R, Gebai A, Tehfe M. Current and Emerging Role of Monoclonal Antibody-Based First-Line Treatment in Advanced Gastro-Esophageal and Gastric Cancer. Curr Oncol 2023; 30:9304-9316. [PMID: 37887572 PMCID: PMC10605724 DOI: 10.3390/curroncol30100672] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Revised: 10/12/2023] [Accepted: 10/19/2023] [Indexed: 10/28/2023] Open
Abstract
Gastric cancer is the fifth most common malignancy worldwide and one of the main causes of cancer-related death. While surgical treatment is the only curative option for early disease, many have inoperable or advanced disease at diagnosis. Treatment in this case would be a combination of chemotherapy and immunotherapy. Gastro-esophageal (GEJ) and gastric cancer (GC) genetic profiling with current molecular diagnostic techniques has significantly changed the therapeutic landscape in advanced cancers. The identification of key players in GEJ and GC survival and proliferation, such as human epidermal growth factor 2 (HER2), vascular endothelial growth factor (VEGF), and programmed cell death protein 1 (PD-1)/programmed cell death ligand-1 (PD-L1), has allowed for the individualization of advanced cancer treatment and significant improvement in overall survival and progression-free survival of patients. This review comprehensively examines the current and emerging role of monoclonal antibody-based first-line treatments in advanced GEJ and GC. We explore the impact of monoclonal antibodies targeting HER2, VEGF, PD-1/PD-L1, and Claudin 18.2 (CLDN18.2) on the first-line treatment landscape by talking about key clinical trials. This review emphasizes the importance of biomarker testing for optimal treatment selection and provides practical recommendations based on ASCO guidelines.
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Affiliation(s)
- Audrey Désilets
- Department of Medicine, Université de Montreal, Montreal, QC H3T 1J4, Canada
| | - Reem Elkhoury
- Department of Medicine, Université de Montreal, Montreal, QC H3T 1J4, Canada
- Hematology-Oncology, Oncology Center-Centre Hospitalier de l’Universite de Montreal, Montreal, QC H2X 0C1, Canada
| | - Ahmad Gebai
- Department of Medicine, Université de Montreal, Montreal, QC H3T 1J4, Canada
| | - Mustapha Tehfe
- Department of Medicine, Université de Montreal, Montreal, QC H3T 1J4, Canada
- Hematology-Oncology, Oncology Center-Centre Hospitalier de l’Universite de Montreal, Montreal, QC H2X 0C1, Canada
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Zhang L, Zhuo H, Hong Z, Hou J, Cheng J, Cai J. HSPA6, a novel prognostic and therapeutic biomarker, associated with Ming classification in gastric cancer. J Clin Lab Anal 2022; 37:e24763. [PMID: 36458368 PMCID: PMC9833989 DOI: 10.1002/jcla.24763] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 10/26/2022] [Accepted: 10/29/2022] [Indexed: 12/04/2022] Open
Abstract
OBJECTIVE This study aimed to explore the clinical relevance of heat shock protein family A member 6 (HSPA6) in gastric cancer (GC) and its effect on GC cell proliferation. METHODS HSPA6 mRNA and protein levels were analyzed by bioinformatics, RT-qPCR, western blot and immunohistochemistry. HSPA6 was correlated with clinicopathological variables by the Chi-square test. Kaplan-Meier survival analysis and the univariate and multivariate Cox models were used to assess the prognostic value of HSPA6. Nomogram was used to predict overall survival in patients with GC. Knockdown or over-expression of HSPA6 in GC cell lines was constructed by lentiviral transduction. EdU and CCK-8 assay were used to detect cell proliferation. In vivo mouse tumor models were performed to evaluate the effects of HSPA6 on GC growth. RESULTS HSPA6 were significantly upregulated in the GC tissues compared to the normal stomach epithelium and were associated with Ming classification (p < 0.001) and tumor size (p = 0.002). Patients with high expression of HSPA6 showed worse survival compared to the low expression group. HSPA6 was identified to be an independent prognostic biomarker for GC. HSPA6 was functionally annotated with the cell cycle, G2M checkpoint and Hippo pathway. Knockdown of HSPA6 suppressed XGC-1 cell proliferation both in vitro and in vivo. Overexpression of HSPA6 in AGS cells increased proliferation rates, increased the levels of cyclinB1 and YAP and decreased that of phosphorylated YAP. HSPA6 knockdown in the NUGC2 cells had the opposite effect. CONCLUSIONS HSPA6 promotes GC proliferation by the Hippo pathway, as a novel prognostic biomarker and potential therapeutic target.
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Affiliation(s)
- Lihua Zhang
- Department of Gastrointestinal SurgeryZhongshan Hospital of Xiamen University, School of Medicine, Xiamen UniversityXiamenChina,Institute of Gastrointestinal Oncology, School of MedicineXiamen UniversityXiamenChina,Xiamen Municipal Key Laboratory of Gastrointestinal OncologyXiamenChina
| | - Hui‐qin Zhuo
- Department of Gastrointestinal SurgeryZhongshan Hospital of Xiamen University, School of Medicine, Xiamen UniversityXiamenChina,Institute of Gastrointestinal Oncology, School of MedicineXiamen UniversityXiamenChina,Xiamen Municipal Key Laboratory of Gastrointestinal OncologyXiamenChina
| | - Zhi‐jun Hong
- Department of Gastrointestinal SurgeryZhongshan Hospital of Xiamen University, School of Medicine, Xiamen UniversityXiamenChina,Institute of Gastrointestinal Oncology, School of MedicineXiamen UniversityXiamenChina,Xiamen Municipal Key Laboratory of Gastrointestinal OncologyXiamenChina
| | - Jing‐jing Hou
- Department of Gastrointestinal SurgeryZhongshan Hospital of Xiamen University, School of Medicine, Xiamen UniversityXiamenChina,Institute of Gastrointestinal Oncology, School of MedicineXiamen UniversityXiamenChina,Xiamen Municipal Key Laboratory of Gastrointestinal OncologyXiamenChina
| | - Jia Cheng
- Department of Gastrointestinal SurgeryZhongshan Hospital of Xiamen University, School of Medicine, Xiamen UniversityXiamenChina,Institute of Gastrointestinal Oncology, School of MedicineXiamen UniversityXiamenChina,Xiamen Municipal Key Laboratory of Gastrointestinal OncologyXiamenChina
| | - Jianchun Cai
- Department of Gastrointestinal SurgeryZhongshan Hospital of Xiamen University, School of Medicine, Xiamen UniversityXiamenChina,Institute of Gastrointestinal Oncology, School of MedicineXiamen UniversityXiamenChina,Xiamen Municipal Key Laboratory of Gastrointestinal OncologyXiamenChina
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Zhang LH, Zhuo HQ, Hou JJ, Zhou Y, Cheng J, Cai JC. Proteomic signatures of infiltrative gastric cancer by proteomic and bioinformatic analysis. World J Gastrointest Oncol 2022; 14:2097-2107. [PMID: 36438703 PMCID: PMC9694269 DOI: 10.4251/wjgo.v14.i11.2097] [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: 03/25/2022] [Revised: 06/16/2022] [Accepted: 10/17/2022] [Indexed: 11/15/2022] Open
Abstract
BACKGROUND Proteomic signatures of Ming's infiltrative gastric cancer (IGC) remain unknown. AIM To elucidate the molecular characteristics of IGC at the proteomics level. METHODS Twelve pairs of IGC and adjacent normal tissues were collected and their proteomes were analyzed by high performance liquid chromatography tandem mass spectrometry. The identified peptides were sequenced de novo and matched against the SwissProt database using Maxquant software. The differentially expressed proteins (DEPs) were screened using |log2(Fold change)| > 1 and P-adj < 0.01 as the thresholds. The expression levels of selected proteins were verified by Western blotting. The interaction network of the DEPs was constructed with the STRING database and visualized using Cytoscape with cytoHubba software. The DEPs were functionally annotated using clusterProfiler, STRING and DAVID for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. P < 0.05 was considered statistically significant. RESULTS A total of 7361 DEPs were identified, of which 94 were significantly up-regulated and 223 were significantly down-regulated in IGC relative to normal gastric tissues. The top 10 up-regulated proteins were MRTO4, BOP1, PES1, WDR12, BRIX1, NOP2, POLR1C, NOC2L, MYBBP1A and TSR1, and the top 10 down-regulated proteins were NDUFS8, NDUFS6, NDUFA8, NDUFA5, NDUFC2, NDUFB8, NDUFB5, NDUFB9, UQCRC2 and UQCRC1. The up-regulated proteins were enriched for 9 biological processes including DNA replication, ribosome biogenesis and initiation of DNA replication, and the cellular component MCM complex. Among the down-regulated proteins, 17 biological processes were enriched, including glucose metabolism, pyruvic acid metabolism and fatty acid β-oxidation. In addition, the mitochondrial inner membrane, mitochondrial matrix and mitochondrial proton transport ATP synthase complex were among the 6 enriched cellular components, and 11 molecular functions including reduced nicotinamide adenine dinucleotide dehydrogenase activity, acyl-CoA dehydrogenase activity and nicotinamide adenine dinucleotide binding were also enriched. The significant KEGG pathways for the up-regulated proteins were DNA replication, cell cycle and mismatch repair, whereas 18 pathways including oxidative phosphorylation, fatty acid degradation and phenylalanine metabolism were significantly enriched among the down-regulated proteins. CONCLUSION The proteins involved in cell cycle regulation, DNA replication and mismatch repair, and metabolism were significantly altered in IGC, and the proteomic profile may enable the discovery of novel biomarkers.
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Affiliation(s)
- Li-Hua Zhang
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361004, Fujian Province, China
- Institute of Gastrointestinal Oncology, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361004, Fujian Province, China
| | - Hui-Qin Zhuo
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361004, Fujian Province, China
- Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen 361004, Fujian Province, China
| | - Jing-Jing Hou
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361004, Fujian Province, China
- Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen 361004, Fujian Province, China
| | - Yang Zhou
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361004, Fujian Province, China
- Institute of Gastrointestinal Oncology, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361004, Fujian Province, China
| | - Jia Cheng
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361004, Fujian Province, China
- Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen 361004, Fujian Province, China
| | - Jian-Chun Cai
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361004, Fujian Province, China
- Institute of Gastrointestinal Oncology, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361004, Fujian Province, China
- Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen 361004, Fujian Province, China
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Staudacher JJ, Arnold A, Kühl AA, Pötzsch M, Daum S, Winterfeld M, Berg E, Hummel M, Rau B, Stein U, Treese C. Prognostic impact of activin subunit inhibin beta A in gastric and esophageal adenocarcinomas. BMC Cancer 2022; 22:953. [PMID: 36064338 PMCID: PMC9446826 DOI: 10.1186/s12885-022-10016-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Accepted: 08/19/2022] [Indexed: 11/10/2022] Open
Abstract
PURPOSE Adenocarcinomas of the esophagus (AEG) and stomach (AS) are among the most common cancers worldwide. Novel markers for risk stratification and guiding treatment are strongly needed. Activin is a multi-functional cytokine with context specific pro- and anti-tumorigenic effects. We aimed to investigate the prognostic role of activin tumor protein expression in AEG/ASs. METHODS Tissue from a retrospective cohort of 277 patients with AEG/AS treated primarily by surgery at the Charité - Universitätsmedizin Berlin was collected and analyzed by immunohistochemistry using a specific antibody to the activin homodimer inhibin beta A. Additionally, we evaluated T-cell infiltration and PD1 expression as well as expression of PD-L1 by immunohistochemistry as possible confounding factors. Clinico-pathologic data were collected and correlated with activin protein expression. RESULTS Out of 277 tumor samples, 72 (26.0%) exhibited high activin subunit inhibin beta A protein expression. Higher expression was correlated with lower Union for International Cancer Control (UICC) stage and longer overall survival. Interestingly, activin subunit expression correlated with CD4+ T-cell infiltration, and the correlation with higher overall survival was exclusively seen in tumors with high CD4+ T-cell infiltration, pointing towards a role of activin in the tumor immune response in AEG/ASs. CONCLUSION In our cohort of AEG/AS, higher activin subunit levels were correlated with longer overall survival, an effect exclusively seen in tumors with high CD4+ cell infiltration. Further mechanistic research is warranted discerning the exact effect of this context specific cytokine.
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Affiliation(s)
- J J Staudacher
- Medical Department, Division of Gastroenterology, Infectious Diseases and Rheumatology, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany.
- Berlin Institute of Health at Charité Universitätsmedizin Berlin, Charitéplatz1, 10117, Berlin, Germany.
| | - Alexander Arnold
- Institute of Pathology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - A A Kühl
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin, iPATH.Berlin, Campus Benjamin Franklin, Berlin, Germany
| | - M Pötzsch
- Medical Department, Division of Gastroenterology, Infectious Diseases and Rheumatology, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany
| | - S Daum
- Medical Department, Division of Gastroenterology, Infectious Diseases and Rheumatology, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany
- Berlin Institute of Health at Charité Universitätsmedizin Berlin, Charitéplatz1, 10117, Berlin, Germany
| | - M Winterfeld
- Institute of Pathology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - E Berg
- Institute of Pathology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - M Hummel
- Institute of Pathology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - B Rau
- Department of Surgery, Campus Virchow-Klinikum and Campus Mitte, Charité - Universitätsmedizin, Berlin, Germany
| | - U Stein
- Experimental and Clinical Research Center, Charité - Universitätsmedizin and Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
- German Cancer Consortium (DKTK), Heidelberg, Germany
| | - C Treese
- Medical Department, Division of Gastroenterology, Infectious Diseases and Rheumatology, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany
- Berlin Institute of Health at Charité Universitätsmedizin Berlin, Charitéplatz1, 10117, Berlin, Germany
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Drubay V, Nuytens F, Renaud F, Adenis A, Eveno C, Piessen G. Poorly cohesive cells gastric carcinoma including signet-ring cell cancer: Updated review of definition, classification and therapeutic management. World J Gastrointest Oncol 2022; 14:1406-1428. [PMID: 36160745 PMCID: PMC9412924 DOI: 10.4251/wjgo.v14.i8.1406] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 05/08/2022] [Accepted: 07/17/2022] [Indexed: 02/05/2023] Open
Abstract
While the incidence of gastric cancer (GC) in general has decreased worldwide in recent decades, the incidence of diffuse cancer historically comprising poorly cohesive cells-GC (PCC-GC) and including signet ring cell cancer is rising. Literature concerning PCC-GC is scarce and unclear, mostly due to a large variety of historically used definitions and classifications. Compared to other histological subtypes of GC, PCC-GC is nevertheless characterized by a distinct set of epidemiological, histological and clinical features which require a specific diagnostic and therapeutic approach. The aim of this review was to provide an update on the definition, classification and therapeutic strategies of PCC-GC. We focus on the updated histological definition of PCC-GC, along with its implications on future treatment strategies and study design. Also, specific considerations in the diagnostic management are discussed. Finally, the impact of some recent developments in the therapeutic management of GC in general such as the recently validated taxane-based regimens (5-Fluorouracil, leucovorin, oxaliplatin and docetaxel), the use of hyperthermic intraperitoneal chemotherapy as well as pressurized intraperitoneal aerosol chemotherapy and targeted therapy have been reviewed in depth for their relative importance for PCC-GC in particular.
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Affiliation(s)
- Vincent Drubay
- Department of Digestive and Oncological Surgery, University Lille, Claude Huriez University Hospital, Lille 59000, France
- Department of Digestive Surgery, Cambrai Hospital Center and Sainte Marie, Group of Hospitals of The Catholic Institute of Lille, Cambrai 59400, France
| | - Frederiek Nuytens
- Department of Digestive and Oncological Surgery, University Lille, Claude Huriez University Hospital, Lille 59000, France
- Department of Digestive and Hepatobiliary/Pancreatic Surgery, AZ Groeninge Hospital, Kortrijk 8500, Belgium
| | - Florence Renaud
- Department of Pathology, University Lille Hospital, Lille 59000, France
- CNRS, Inserm, UMR9020-U1277-CANTHER-Cancer, University Lille, CHU Lille, Lille 59000, France
- FREGAT Network, Claude Huriez University Hospital, Lille 59000, France
| | - Antoine Adenis
- FREGAT Network, Claude Huriez University Hospital, Lille 59000, France
- Department of Medical Oncology, Montpellier Cancer Institute, Monpellier 34000, France
- IRCM, Inserm, University of Monpellier, Monpellier 34000, France
| | - Clarisse Eveno
- Department of Digestive and Oncological Surgery, University Lille, Claude Huriez University Hospital, Lille 59000, France
- CNRS, Inserm, UMR9020-U1277-CANTHER-Cancer, University Lille, CHU Lille, Lille 59000, France
- FREGAT Network, Claude Huriez University Hospital, Lille 59000, France
| | - Guillaume Piessen
- Department of Digestive and Oncological Surgery, University Lille, Claude Huriez University Hospital, Lille 59000, France
- CNRS, Inserm, UMR9020-U1277-CANTHER-Cancer, University Lille, CHU Lille, Lille 59000, France
- FREGAT Network, Claude Huriez University Hospital, Lille 59000, France
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Lu Y, Cheng J, Cai W, Zhuo H, Wu G, Cai J. Inhibition of circRNA circVPS33B Reduces Warburg Effect and Tumor Growth Through Regulating the miR-873-5p/HNRNPK Axis in Infiltrative Gastric Cancer. Onco Targets Ther 2021; 14:3095-3108. [PMID: 34012268 PMCID: PMC8126971 DOI: 10.2147/ott.s292575] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Accepted: 04/02/2021] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Circular RNA VPS33B (circVPS33B) has been revealed to be upregulated in gastric cancer (GC) tissues. However, the role of circVPS33B in infiltrative GC is indistinct. METHODS Expression of circVPS33B was detected using quantitative real-time polymerase chain reaction (qRT-PCR). The proliferation, migration, and invasion of infiltrative GC cells (XGC-1) were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT), plate clone, wound-healing, or transwell assays. Protein levels were detected by Western blotting. Measurements of extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) were executed using an XF96 extracellular flux analyzer. Glucose uptake and lactate production were analyzed by glycolysis assay. The regulatory mechanism of circVPS33B had been explored by bioinformatics analysis, dual-luciferase reporter assay, and/or RNA pull-down assay. In vivo tumorigenesis assay was executed to verify the oncogenicity of circVPS33B. RESULTS CircVPS33B was upregulated in infiltrative GC tissues and cells. CircVPS33B silencing decreased tumor growth in vivo and inhibited proliferation, migration, invasion, EMT, and Warburg effect of infiltrative GC cells in vitro. Mechanically, circVPS33B regulated heterogeneous nuclear ribonucleoprotein K (HNRNPK) expression via sponging miR-873-5p. Furthermore, miR-873-5p inhibitor offset circVPS33B knockdown-mediated effects on malignant behaviors and Warburg effect of infiltrative GC cells. HNRNPK overexpression reversed the inhibitory impact of miR-873-5p mimic on malignant behaviors and Warburg effect of infiltrative GC cells. CONCLUSION CircVPS33B accelerated Warburg effect and tumor growth through regulating the miR-873-5p/HNRNPK axis in infiltrative GC, manifesting that circVPS33B might be a potential target for infiltrative GC treatment.
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Affiliation(s)
- Yizhuo Lu
- Department of General Surgery, Zhongshan Hospital Xiamen University, Institute of Gastrointestinal Oncology, School of Medicine, Xiamen University, Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen, Fujian, 361004, People’s Republic of China
| | - Jia Cheng
- Department of Gastrointestinal Surgery, Zhongshan Hospital Xiamen University, Institute of Gastrointestinal Oncology, School of Medicine, Xiamen University, Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen, Fujian, 361004, People’s Republic of China
| | - Wangyu Cai
- Department of Gastrointestinal Surgery, Zhongshan Hospital Xiamen University, Institute of Gastrointestinal Oncology, School of Medicine, Xiamen University, Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen, Fujian, 361004, People’s Republic of China
| | - Huiqin Zhuo
- Department of Gastrointestinal Surgery, Zhongshan Hospital Xiamen University, Institute of Gastrointestinal Oncology, School of Medicine, Xiamen University, Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen, Fujian, 361004, People’s Republic of China
| | - Guoyang Wu
- Department of General Surgery, Zhongshan Hospital Xiamen University, Institute of Gastrointestinal Oncology, School of Medicine, Xiamen University, Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen, Fujian, 361004, People’s Republic of China
| | - Jianchun Cai
- Department of Gastrointestinal Surgery, Zhongshan Hospital Xiamen University, Institute of Gastrointestinal Oncology, School of Medicine, Xiamen University, Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen, Fujian, 361004, People’s Republic of China
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Busuttil RA, George J, House CM, Lade S, Mitchell C, Di Costanzo NS, Pattison S, Huang YK, Tan P, Cheong JH, Rha SY, Boussioutas A. SFRP4 drives invasion in gastric cancer and is an early predictor of recurrence. Gastric Cancer 2021; 24:589-601. [PMID: 33277667 PMCID: PMC8064978 DOI: 10.1007/s10120-020-01143-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Accepted: 11/14/2020] [Indexed: 02/07/2023]
Abstract
OBJECTIVE Gastric cancer patients generally have a poor outcome, particularly those with advanced-stage disease which is defined by the increased invasion of cancer locally and is associated with higher metastatic potential. This study aimed to identify genes that were functional in the most fundamental hallmark of cancer, namely invasion. We then wanted to assess their value as biomarkers of gastric cancer progression and recurrence. DESIGN Data from a cohort of patients profiled on cDNA expression arrays was interrogated using K-means analysis. This genomic approach classified the data based on patterns of gene expression allowing the identification of the genes most correlated with the invasion of GC. We evaluated the functional role of a key protein from this analysis in invasion and as a biomarker of recurrence after curative resection. RESULTS Expression of secreted frizzled-related protein 4 (SFRP4) was identified as directly proportional to gastric cancer invasion. This finding was validated in multiple, independent datasets and its functional role in invasion was also confirmed using invasion assays. A change in serum levels of SFRP4 after curative resection, when coupled with AJCC stage, can accurately predict the risk of disease recurrence after curative therapy in an assay we termed PredictR. CONCLUSIONS This simple ELISA-based assay can help predict recurrence of disease after curative gastric cancer surgery irrespective of adjuvant therapy. The results require further evaluation in a prospective trial but would help in the rational prescription of cancer therapies and surveillance to prevent under or over treatment of patients after curative resection.
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Affiliation(s)
- Rita A Busuttil
- Upper Gastrointestinal Translational Research Laboratory, Peter MacCallum Cancer Centre, 305 Grattan St, Parkville, VIC, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia
- Department of Medicine, The University of Melbourne, Parkville, VIC, Australia
| | - Joshy George
- Computational Sciences, Jackson Laboratory for Genomic Medicine, Farmington, USA
| | - Colin M House
- Upper Gastrointestinal Translational Research Laboratory, Peter MacCallum Cancer Centre, 305 Grattan St, Parkville, VIC, Australia
| | - Stephen Lade
- Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia
| | - Catherine Mitchell
- Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia
| | - Natasha S Di Costanzo
- Upper Gastrointestinal Translational Research Laboratory, Peter MacCallum Cancer Centre, 305 Grattan St, Parkville, VIC, Australia
| | - Sharon Pattison
- Department of Medicine, University of Otago, Dunedin, New Zealand
| | - Yu-Kuan Huang
- Upper Gastrointestinal Translational Research Laboratory, Peter MacCallum Cancer Centre, 305 Grattan St, Parkville, VIC, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia
- Department of Medicine, The University of Melbourne, Parkville, VIC, Australia
| | - Patrick Tan
- Genome Institute of Singapore, Singapore, Singapore
- Cancer Science Institute of Singapore, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Jae-Ho Cheong
- Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea
- Department of Biomedical Systems Informatics, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Sun Young Rha
- Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Alex Boussioutas
- Upper Gastrointestinal Translational Research Laboratory, Peter MacCallum Cancer Centre, 305 Grattan St, Parkville, VIC, Australia.
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia.
- Department of Medicine, The University of Melbourne, Parkville, VIC, Australia.
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10
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Quirino MWL, Pereira MC, Deodato de Souza MDF, Pitta IDR, Da Silva Filho AF, Albuquerque MSDS, Albuquerque APDB, Martins MR, Pitta MGDR, Rêgo MJBDM. Immunopositivity for Siglec-15 in gastric cancer and its association with clinical and pathological parameters. Eur J Histochem 2021; 65. [PMID: 33666065 PMCID: PMC7967265 DOI: 10.4081/ejh.2021.3174] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2020] [Accepted: 02/09/2021] [Indexed: 01/03/2023] Open
Abstract
The sialic acid-binding immunoglobulin-type lectin Siglec-15 is a promising target for cancer immunotherapy in several tumor types. The present study aimed to investigate Siglec-15 expression in gastric cancer (GC) patient tissues and to evaluate its clinical value. Siglec-15 expression was evaluated by immunohistochemistry in 71 patients. Siglec-15 staining was observed in tumor cells of 53 (74.64%) patients, with significant association with histologic classification and angiolymphatic invasion (p<0.05). Immunohistochemistry analysis also detected Siglec-15 in tumor-associated stroma cells (macrophages/myeloid cells). There was no significant association with outcome parameters. Siglec-15 expression in well differentiated histological GC tissues and in the tumor microenvironment are potential targets to be further investigated as a novel prognostic factor for GC.
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Affiliation(s)
- Michael Williams Leal Quirino
- Laboratório de Imunomodulação e Novas Abordagens Terapêuticas - LINAT / Núcleo de Pesquisa em Inovação Terapêutica Suely Galdino - NUPIT SG, Universidade Federal de Pernambuco, Recife.
| | - Michelly Cristiny Pereira
- Laboratório de Imunomodulação e Novas Abordagens Terapêuticas - LINAT / Núcleo de Pesquisa em Inovação Terapêutica Suely Galdino - NUPIT SG, Universidade Federal de Pernambuco, Recife.
| | - Maria de Fátima Deodato de Souza
- Laboratório de Imunomodulação e Novas Abordagens Terapêuticas - LINAT / Núcleo de Pesquisa em Inovação Terapêutica Suely Galdino - NUPIT SG, Universidade Federal de Pernambuco, Recife.
| | - Ivan da Rocha Pitta
- Laboratório de Imunomodulação e Novas Abordagens Terapêuticas - LINAT / Núcleo de Pesquisa em Inovação Terapêutica Suely Galdino - NUPIT SG, Universidade Federal de Pernambuco, Recife.
| | - Antônio Felix Da Silva Filho
- Laboratório de Imunomodulação e Novas Abordagens Terapêuticas - LINAT / Núcleo de Pesquisa em Inovação Terapêutica Suely Galdino - NUPIT SG, Universidade Federal de Pernambuco, Recife.
| | - Mario S de Souza Albuquerque
- Laboratório de Imunomodulação e Novas Abordagens Terapêuticas - LINAT / Núcleo de Pesquisa em Inovação Terapêutica Suely Galdino - NUPIT SG, Universidade Federal de Pernambuco, Recife.
| | - Amanda Pinheiro de Barros Albuquerque
- Laboratório de Imunomodulação e Novas Abordagens Terapêuticas - LINAT / Núcleo de Pesquisa em Inovação Terapêutica Suely Galdino - NUPIT SG, Universidade Federal de Pernambuco, Recife.
| | | | - Maira Galdino da Rocha Pitta
- Laboratório de Imunomodulação e Novas Abordagens Terapêuticas - LINAT / Núcleo de Pesquisa em Inovação Terapêutica Suely Galdino - NUPIT SG, Universidade Federal de Pernambuco, Recife.
| | - Moacyr Jesus Barreto de Melo Rêgo
- Laboratório de Imunomodulação e Novas Abordagens Terapêuticas - LINAT / Núcleo de Pesquisa em Inovação Terapêutica Suely Galdino - NUPIT SG, Universidade Federal de Pernambuco, Recife.
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11
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Mao D, Zhou Z, Song S, Li D, He Y, Wei Z, Zhang C. Identification of Stemness Characteristics Associated With the Immune Microenvironment and Prognosis in Gastric Cancer. Front Oncol 2021; 11:626961. [PMID: 33747944 PMCID: PMC7966731 DOI: 10.3389/fonc.2021.626961] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2020] [Accepted: 01/25/2021] [Indexed: 12/24/2022] Open
Abstract
Background Gastric cancer (GC) is a highly heterogeneous disease. In recent years, the prognostic value of the mRNA expression-based stemness index (mRNAsi) across cancers has been reported. We intended to identify stemness index-associated genes (SI-genes) for clinical characteristic, gene mutation status, immune response, and tumor microenvironment evaluation as well as risk stratification and survival prediction. Methods The correlations between the mRNAsi and GC prognosis, clinical characteristics, gene mutation status, immune cell infiltration and tumor microenvironment were evaluated. Weighted gene correlation network analysis (WGCNA) was performed to identify SI-genes from differentially expressed genes (DEGs) in The Cancer Genome Atlas (TCGA). Single-sample gene set enrichment analysis (ssGSEA) was employed to calculate the sample SI-gene-based ssGSEA score according to the SI-genes. Then, the correlations between the ssGSEA score and GC prognosis, clinical characteristics, gene mutation status, immune cell infiltration and tumor microenvironment were analyzed. Finally, the least absolute shrinkage and selection operator (LASSO) Cox regression algorithm was used to construct a prognostic signature with prognostic SI-genes. The ssGSEA score and prognostic signature were validated using the Gene Expression Omnibus (GEO) database. Results The mRNAsi could predict overall survival (OS), clinical characteristics, the gene mutation status, immune cell infiltration, and the tumor microenvironment composition. Fourteen positive SI-genes and 178 negative SI-genes were screened out using WGCNA. The ssGSEA score, similar to the mRNAsi, was found to be closely related to OS, clinical characteristics, the gene mutation status, immune cell infiltration, and the tumor microenvironment composition. Finally, a prognostic signature based on 18 prognostic SI-genes was verified to more accurately predict GC 1-year, 3-year, and 5-year OS than traditional clinical prediction models. Conclusion The ssGSEA score and prognostic signature based on 18 prognostic SI-genes are of great value for immune response evaluation, risk stratification and survival prediction in GC and suggest that stemness features are crucial drivers of GC progression.
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Affiliation(s)
- Deli Mao
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Zhijun Zhou
- Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
| | - Shenglei Song
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Dongsheng Li
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Yulong He
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Zhewei Wei
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Changhua Zhang
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
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12
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Businello G, Galuppini F, Fassan M. The impact of recent next generation sequencing and the need for a new classification in gastric cancer. Best Pract Res Clin Gastroenterol 2021; 50-51:101730. [PMID: 33975684 DOI: 10.1016/j.bpg.2021.101730] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Revised: 01/27/2021] [Accepted: 02/09/2021] [Indexed: 02/06/2023]
Abstract
The phenotypical and molecular heterogeneity of gastric cancer has hampered the introduction in clinical practice of a unifying classification of the disease. However, as next generation sequencing (NGS) technologies enhanced the comprehension of the molecular landscape of gastric cancer, novel molecular classification systems have been proposed, allowing the dissection of molecular tumor heterogeneity and paving the way for the development of new targeted therapies. Moreover, the use of NGS analyses in the molecular profiling of formalin-fixed paraffin-embedded (FFPE) specimens will improve patient selection for the enrolment in novel clinical trials. In conclusion, the application of NGS in precision oncology will revolutionize the diagnosis and clinical management in gastric cancer patients.
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Affiliation(s)
- Gianluca Businello
- Department of Medicine (DIMED), Surgical Pathology & Cytopathology Unit, University of Padua, Padua, Italy
| | - Francesca Galuppini
- Department of Medicine (DIMED), Surgical Pathology & Cytopathology Unit, University of Padua, Padua, Italy
| | - Matteo Fassan
- Department of Medicine (DIMED), Surgical Pathology & Cytopathology Unit, University of Padua, Padua, Italy.
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13
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Blessin NC, Spriestersbach P, Li W, Mandelkow T, Dum D, Simon R, Hube-Magg C, Lutz F, Viehweger F, Lennartz M, Fraune C, Nickelsen V, Fehrle W, Göbel C, Weidemann S, Clauditz T, Lebok P, Möller K, Steurer S, Izbicki JR, Sauter G, Minner S, Jacobsen F, Luebke AM, Büscheck F, Höflmayer D, Wilczak W, Burandt E, Hinsch A. Prevalence of CD8 + cytotoxic lymphocytes in human neoplasms. Cell Oncol (Dordr) 2020; 43:421-430. [PMID: 32141029 PMCID: PMC7214387 DOI: 10.1007/s13402-020-00496-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/07/2020] [Indexed: 12/17/2022] Open
Abstract
PURPOSE Immune checkpoint inhibitors have recently been approved by the US FDA as first and/or second line therapy in a subset of cancer types. Recent evidence suggests that the quantity of tumor infiltrating lymphocytes (TILs) influences the likelihood of response to immune checkpoint inhibitors. Here, we set out to assess the density of CD8+ lymphocytes in a wide range of different cancer types and subtypes. METHODS The density of CD8+ lymphocytes was compared across different cancer types using tissue microarrays (TMAs) composed of up to 50 tumor samples each from 84 different cancer types and subtypes. In total 2652 cancers and 608 normal tissues were successfully analyzed by CD8 immunohistochemistry followed by automated image analysis of digitized slides. RESULTS We found that the median CD8+ lymphocyte counts ranged from 6 cells/mm2 in pleomorphic adenoma up to 1573 cells/mm2 in Hodgkin's lymphoma. The CD8 counts were generally lower in normal tissues compared to cancer tissues. Blood vessels of the spleen were the only non-lymphatic tissue staining positive for CD8. Tumor types approved for checkpoint inhibitor therapy, including malignant melanoma (81), muscle invasive urothelial carcinoma (119), small cell lung cancer (120), clear cell renal cell cancer (153), squamous cell carcinoma (189) and adenocarcinoma of the lung (328) as well as Hodgkin's lymphoma (1573) were all ranking among the upper half of our list. Comparably high CD8 densities (median cells/mm2) were also found in several rare and aggressive cancer types including Merkel cell carcinoma (70), angiosarcoma (95), anaplastic thyroid cancer (156) and embryonal carcinoma of the testis (186). In 73 of the 84 analyzed cancer types, the highly variable CD8 counts occasionally exceeded the average CD8 count of tumors for which checkpoint inhibitors have been approved. CONCLUSION These data support the concept that among most tumor types at least some individual cancers may benefit from treatment with immune checkpoint inhibitors.
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Affiliation(s)
- Niclas C Blessin
- Institute of Pathology, Martinistraße 52, University Medical Center Hamburg-Eppendorf, D-20246, Hamburg, Germany
| | - Patrick Spriestersbach
- Institute of Pathology, Martinistraße 52, University Medical Center Hamburg-Eppendorf, D-20246, Hamburg, Germany
| | - Wenchao Li
- Institute of Pathology, Martinistraße 52, University Medical Center Hamburg-Eppendorf, D-20246, Hamburg, Germany
| | - Tim Mandelkow
- Institute of Pathology, Martinistraße 52, University Medical Center Hamburg-Eppendorf, D-20246, Hamburg, Germany
| | - David Dum
- Institute of Pathology, Martinistraße 52, University Medical Center Hamburg-Eppendorf, D-20246, Hamburg, Germany
| | - Ronald Simon
- Institute of Pathology, Martinistraße 52, University Medical Center Hamburg-Eppendorf, D-20246, Hamburg, Germany.
| | - Claudia Hube-Magg
- Institute of Pathology, Martinistraße 52, University Medical Center Hamburg-Eppendorf, D-20246, Hamburg, Germany
| | - Florian Lutz
- Institute of Pathology, Martinistraße 52, University Medical Center Hamburg-Eppendorf, D-20246, Hamburg, Germany
| | - Florian Viehweger
- Institute of Pathology, Martinistraße 52, University Medical Center Hamburg-Eppendorf, D-20246, Hamburg, Germany
| | - Maximillian Lennartz
- Institute of Pathology, Martinistraße 52, University Medical Center Hamburg-Eppendorf, D-20246, Hamburg, Germany
| | - Christoph Fraune
- Institute of Pathology, Martinistraße 52, University Medical Center Hamburg-Eppendorf, D-20246, Hamburg, Germany
| | - Vera Nickelsen
- Institute of Pathology, Martinistraße 52, University Medical Center Hamburg-Eppendorf, D-20246, Hamburg, Germany
| | - Wilfried Fehrle
- Institute of Pathology, Martinistraße 52, University Medical Center Hamburg-Eppendorf, D-20246, Hamburg, Germany
| | - Cosima Göbel
- Institute of Pathology, Martinistraße 52, University Medical Center Hamburg-Eppendorf, D-20246, Hamburg, Germany
| | - Sören Weidemann
- Institute of Pathology, Martinistraße 52, University Medical Center Hamburg-Eppendorf, D-20246, Hamburg, Germany
| | - Till Clauditz
- Institute of Pathology, Martinistraße 52, University Medical Center Hamburg-Eppendorf, D-20246, Hamburg, Germany
| | - Patrick Lebok
- Institute of Pathology, Martinistraße 52, University Medical Center Hamburg-Eppendorf, D-20246, Hamburg, Germany
| | - Katharina Möller
- Institute of Pathology, Martinistraße 52, University Medical Center Hamburg-Eppendorf, D-20246, Hamburg, Germany
| | - Stefan Steurer
- Institute of Pathology, Martinistraße 52, University Medical Center Hamburg-Eppendorf, D-20246, Hamburg, Germany
| | - Jacob R Izbicki
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Guido Sauter
- Institute of Pathology, Martinistraße 52, University Medical Center Hamburg-Eppendorf, D-20246, Hamburg, Germany
| | - Sarah Minner
- Institute of Pathology, Martinistraße 52, University Medical Center Hamburg-Eppendorf, D-20246, Hamburg, Germany
| | - Frank Jacobsen
- Institute of Pathology, Martinistraße 52, University Medical Center Hamburg-Eppendorf, D-20246, Hamburg, Germany
| | - Andreas M Luebke
- Institute of Pathology, Martinistraße 52, University Medical Center Hamburg-Eppendorf, D-20246, Hamburg, Germany
| | - Franziska Büscheck
- Institute of Pathology, Martinistraße 52, University Medical Center Hamburg-Eppendorf, D-20246, Hamburg, Germany
| | - Doris Höflmayer
- Institute of Pathology, Martinistraße 52, University Medical Center Hamburg-Eppendorf, D-20246, Hamburg, Germany
| | - Waldemar Wilczak
- Institute of Pathology, Martinistraße 52, University Medical Center Hamburg-Eppendorf, D-20246, Hamburg, Germany
| | - Eike Burandt
- Institute of Pathology, Martinistraße 52, University Medical Center Hamburg-Eppendorf, D-20246, Hamburg, Germany
| | - Andrea Hinsch
- Institute of Pathology, Martinistraße 52, University Medical Center Hamburg-Eppendorf, D-20246, Hamburg, Germany
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14
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Cheng J, Zhuo H, Xu M, Wang L, Xu H, Peng J, Hou J, Lin L, Cai J. Regulatory network of circRNA-miRNA-mRNA contributes to the histological classification and disease progression in gastric cancer. J Transl Med 2018; 16:216. [PMID: 30068360 PMCID: PMC6071397 DOI: 10.1186/s12967-018-1582-8] [Citation(s) in RCA: 138] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2018] [Accepted: 07/17/2018] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Little has been known about the role of non-coding RNA regulatory network in the patterns of growth and invasiveness of gastric cancer (GC) development. METHODS MicroRNAs (miRNAs) microarray was used to screen differential miRNA expression profiles in Ming's classification. The significant differential expressions of representative miRNAs and their interacting circular RNA (circRNA) were confirmed in GC cell line and 63 pairs of GC samples. Then, a circRNA/miRNA network was constructed by bioinformatics approaches to identify molecular pathways. Finally, we explored the clinical value of the common targets in the pathway by using receiver operating characteristic curve and survival analysis. RESULTS Significantly differential expressed miRNAs were found in two pathological types of GC. Both of miR-124 and miR-29b were consistently down-regulated in GC. CircHIPK3 could play a negative regulatory role on miR-124/miR-29b expression and associated with T stage and Ming's classification in GC. The bioinformatics analyses showed that targets expression of circHIPK3-miR-124/miR-29b axes in cancer-related pathways was able to predict the status of GC and associated with individual survival time. CONCLUSIONS The targets of circHIPK3-miR-124/miR-29b axes involved in the progression of GC. CircHIPK3 could take part in the proliferation process of GC cell and may be potential biomarker in histological classification of GC.
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Affiliation(s)
- Jia Cheng
- Department of Gastrointestinal Surgery, Zhongshan Hospital, Xiamen University, Xiamen, 361004 Fujian China
- Institute of Gastrointestinal Oncology, Medical College of Xiamen University, Xiamen, 361004 Fujian China
- Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen, 361004 Fujian China
| | - Huiqin Zhuo
- Department of Gastrointestinal Surgery, Zhongshan Hospital, Xiamen University, Xiamen, 361004 Fujian China
- Institute of Gastrointestinal Oncology, Medical College of Xiamen University, Xiamen, 361004 Fujian China
- Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen, 361004 Fujian China
| | - Mao Xu
- Department of Gastrointestinal Surgery, Zhongshan Hospital, Xiamen University, Xiamen, 361004 Fujian China
- Institute of Gastrointestinal Oncology, Medical College of Xiamen University, Xiamen, 361004 Fujian China
- Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen, 361004 Fujian China
| | - Linpei Wang
- Department of Gastrointestinal Surgery, Zhongshan Hospital, Xiamen University, Xiamen, 361004 Fujian China
- Institute of Gastrointestinal Oncology, Medical College of Xiamen University, Xiamen, 361004 Fujian China
| | - Hao Xu
- Department of Gastrointestinal Surgery, Zhongshan Hospital, Xiamen University, Xiamen, 361004 Fujian China
- Institute of Gastrointestinal Oncology, Medical College of Xiamen University, Xiamen, 361004 Fujian China
| | - Jigui Peng
- Department of Gastrointestinal Surgery, Zhongshan Hospital, Xiamen University, Xiamen, 361004 Fujian China
- Institute of Gastrointestinal Oncology, Medical College of Xiamen University, Xiamen, 361004 Fujian China
| | - Jingjing Hou
- Department of Gastrointestinal Surgery, Zhongshan Hospital, Xiamen University, Xiamen, 361004 Fujian China
- Institute of Gastrointestinal Oncology, Medical College of Xiamen University, Xiamen, 361004 Fujian China
- Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen, 361004 Fujian China
| | - Lingyun Lin
- Department of Gastrointestinal Surgery, Zhongshan Hospital, Xiamen University, Xiamen, 361004 Fujian China
- Institute of Gastrointestinal Oncology, Medical College of Xiamen University, Xiamen, 361004 Fujian China
- Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen, 361004 Fujian China
| | - Jianchun Cai
- Department of Gastrointestinal Surgery, Zhongshan Hospital, Xiamen University, Xiamen, 361004 Fujian China
- Institute of Gastrointestinal Oncology, Medical College of Xiamen University, Xiamen, 361004 Fujian China
- Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen, 361004 Fujian China
- Union Hospital, Fujian Medical University, Fuzhou, 350001 Fujian China
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15
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Prognostic risk factors of early gastric cancer-a western experience. Langenbecks Arch Surg 2016; 401:667-76. [PMID: 27074726 DOI: 10.1007/s00423-016-1395-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2015] [Accepted: 02/29/2016] [Indexed: 02/07/2023]
Abstract
PURPOSE Lymph node metastasis (LNM) is the leading cause of tumor recurrence in early gastric cancer (EGC). Since endoscopic resection (ER) can be performed in EGC with curative intention when no LNM are present, this study wants to determine the risk factors for LNM in EGC. METHODS One hundred twenty-four patients who have had an operative resection because of EGC were analyzed. Histopathological workup included tumor infiltration depth, lymphatic and vascular infiltration, lymph node infiltration, tumor differentiation, and the classification of Ming. A complete follow-up was achieved. RESULTS There was no LNM among tumors meeting the standard or extended criteria for an ER. Lymphatic infiltration (p < 0.001) and infiltration of the submucosal layers (p = 0.018) proved to be the strongest risk factors for LNM. Tumors with a deeper infiltration depth (p = 0.015) and a lower grade of differentiation (p = 0.029) presented with a higher grade of lymphatic infiltration. Tumors located in the body of the stomach (p = 0.003) and tumors with infiltrative growth according to Ming (p = 0.021) had a significantly higher risk for lymphatic infiltration. The 5-year overall survival was 84 % in nodal negative patients and 42 % in patients with LNM (p = 0.002). CONCLUSIONS ER within the extended criteria with a meticulous histological workup should be performed in EGC to determine whether risk factors for LNM are present. If lymphatic infiltration is observed, surgery with lymphadenectomy is recommended. Tumors exceeding the extended criteria should undergo primary surgery with adequate lymphadenectomy.
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16
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Kim HW, Won KS, Song BI, Kang YN. Correlation of Primary Tumor FDG Uptake with Histopathologic Features of Advanced Gastric Cancer. Nucl Med Mol Imaging 2015; 49:135-42. [PMID: 26085859 DOI: 10.1007/s13139-015-0327-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2014] [Revised: 01/05/2015] [Accepted: 02/13/2015] [Indexed: 12/18/2022] Open
Abstract
PURPOSE Histopathologic features could affect the FDG uptake of primary gastric cancer and detection rate on FDG PET/CT. The aim of this study was to evaluate the FDG uptake of primary gastric cancer by correlating it with the histopathologic features of the tumors. METHODS Fifty patients with locally advanced gastric adenocarcinoma who were referred for preoperative FDG-PET/CT scans were enrolled in this study. The detection rate of PET/CT and maximum standardized uptake values (SUVmax) of the primary tumor were compared using the WHO, Lauren, Ming and Borrmann classifications and tumor size and location. RESULTS In 45 of the 50 patients (90 %), the primary gastric tumors were detected by FDG PET/CT. On comparison using the WHO classification, the detection rate and SUVmax of the tubular type were significantly higher than those of the poorly cohesive type. On comparison using the Lauren and Ming classifications, the SUVmaxs of the intestinal type and expanding type were significantly higher than those of the diffuse and infiltrative type, respectively. On comparison using the Borrmann classification and tumor size and location, there was no significant difference in the detection rate and SUVmax of primary gastric tumors. CONCLUSION This study demonstrates that the poorly cohesive type according to the WHO classification, diffuse type according to the Lauren classification and infiltrative type according to the Ming classification have low FDG uptake in patients with locally advanced gastric carcinoma. Understanding the relationship between primary tumor FDG uptake and histopathologic features would be helpful in detecting the primary tumor by FDG PET/CT in patients with gastric cancer.
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Affiliation(s)
- Hae Won Kim
- Department of Nuclear Medicine, Keimyung University Dongsan Medical Center, 56 Dalseong-ro, Jung-Gu, Daegu Republic of Korea
| | - Kyoung Sook Won
- Department of Nuclear Medicine, Keimyung University Dongsan Medical Center, 56 Dalseong-ro, Jung-Gu, Daegu Republic of Korea
| | - Bong-Il Song
- Department of Nuclear Medicine, Keimyung University Dongsan Medical Center, 56 Dalseong-ro, Jung-Gu, Daegu Republic of Korea
| | - Yu Na Kang
- Department of Pathology, Keimyung University Dongsan Medical Center, Jung-Gu, South Korea
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Yu JL, Lv P, Han J, Zhu X, Hong LL, Zhu WY, Wang XB, Wu YC, Li P, Ling ZQ. Methylated TIMP-3 DNA in body fluids is an independent prognostic factor for gastric cancer. Arch Pathol Lab Med 2015; 138:1466-73. [PMID: 25357107 DOI: 10.5858/arpa.2013-0285-oa] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
CONTEXT Fluid methylated DNA may be a suitable biomarker for cancer patients. OBJECTIVE To investigate whether circulating methylated tissue inhibitor of metalloproteinase 3 (TIMP-3) DNA in body fluids is a useful prognostic biomarker in gastric cancer (GC). DESIGN TIMP-3 methylation was detected by real-time methylation-specific polymerase chain reaction in tumor tissues, paired preoperative peritoneal washes (PPWs), and paired serum samples from 92 GC patients. RESULTS The frequency of TIMP-3 methylation was significantly elevated in GC tissues (63.04%; 58 of 92) compared with that in paired adjacent normal tissue (4.3%; 4 of 92) (P < .001). TIMP-3 methylation correlated closely with peritoneal metastasis and TNM stage (all P < .001). The frequency of TIMP-3 methylation in preoperative peritoneal washes and serum samples was 53.3% (49 of 92) and 58.7% (54 of 92), respectively. The Aζ values of the receiver operator characteristic curve for methylated TIMP-3 were 0.966 and 0.922 for serum and preoperative peritoneal washes, respectively, compared with those in GC tissues. The patients with elevated methylated TIMP-3 levels in body fluids had poorer disease-free survival rates than those without (all P < .001). Cox regression analysis showed that detection of methylated TIMP-3 DNA in body fluids was an independent risk factor for GC patients, with a remarkable decrease in disease-free survival 30 months after surgical resection of the gastric tumor. CONCLUSION Presence of methylated TIMP-3 DNA in body fluids is a useful biomarker for predicting the progression and prognosis of GC patients.
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Affiliation(s)
- Jiang-Liu Yu
- From the Zhejiang Cancer Research Institute (Drs Yu, Han, X. Zhu, Wu, Hong, and Ling) and the Department of Surgical Oncology (Dr Wang), Zhejiang Province Cancer Hospital, Zhejiang Cancer Center, Hangzhou, China; the Department of Surgical Oncology (Dr Lv) and the Central Laboratory (Dr W-Y Zhu), Zhoushan Hospital, Zhoushan, China; and the Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China (Dr Li)
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Lee SY, Kim DW, Lee HS, Ihn MH, Oh HK, Park DJ, Kim HH, Kang SB. Loss of AT-rich interactive domain 1A expression in gastrointestinal malignancies. Oncology 2014; 88:234-40. [PMID: 25503393 DOI: 10.1159/000369140] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2014] [Accepted: 10/10/2014] [Indexed: 11/19/2022]
Abstract
OBJECTIVE AT-rich interactive domain 1A (ARID1A) has recently been identified as a novel tumor suppressor in various tumor types. This study was designed to explore the clinical relevance and prognostic impact of ARID1A expression loss in colorectal cancer (CRC) and gastric cancer (GC). METHODS Immunohistochemistry for ARID1A was performed using tissue microarray blocks containing 196 CRCs and 275 GCs, along with paired normal mucosa. Data on clinicopathologic variables and oncologic outcomes of patients were collected and analyzed. RESULTS We identified 6.1% (12/196) CRC and 8.0% (22/275) GC cases showing loss of ARID1A expression. Expression of ARID1A in paired mucosal epithelial cells was normal in all patients. Loss of ARID1A expression was significantly correlated with negative lymphatic invasion (p = 0.003) in CRC, with large tumor size (p = 0.037) in GC, and with expanding tumor border in both tumor types (CRC, p = 0.010; GC, p = 0.031). However, no association was evident between ARID1A expression and 5-year overall survival in both tumor types. CONCLUSIONS Loss of ARID1A expression is uncommon and not associated with oncologic outcome but may be related to less invasive clinicopathologic features in CRC and GC. Further studies with a larger number of subjects are needed to establish the possible prognostic impact of ARID1A expression loss.
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Affiliation(s)
- Soo Young Lee
- Department of Surgery, Chonnam National University Hwasun Hospital, Hwasun, South Korea
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Domschke P, Trucu D, Gerisch A, A. J. Chaplain M. Mathematical modelling of cancer invasion: Implications of cell adhesion variability for tumour infiltrative growth patterns. J Theor Biol 2014; 361:41-60. [DOI: 10.1016/j.jtbi.2014.07.010] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2014] [Revised: 07/05/2014] [Accepted: 07/07/2014] [Indexed: 10/25/2022]
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Circulating methylated MINT2 promoter DNA is a potential poor prognostic factor in gastric cancer. Dig Dis Sci 2014; 59:1160-8. [PMID: 24385013 DOI: 10.1007/s10620-013-3007-0] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2013] [Accepted: 12/17/2013] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIM Aberrant DNA methylation has been shown to be associated with the growth, development, metastasis, and prognosis of tumors. Methylated DNAs may be suitable biomarkers for cancer patients. Here, we investigated whether circulating methylated MINT2 DNAs represent a potential poor prognostic factor in gastric cancer (GC). METHODS MINT2 methylation was detected by real-time methylation-specific PCR in tumor tissues, pairing preoperative peritoneal lavage fluid (PPLF) and blood from 92 GC patients. The theory meaning and clinical practicality value of MINT2 methylation in different specimens were analyzed. RESULTS The methylation status of the MINT2 gene was found to be significantly higher in tumor tissues (44.6%, 41/92) than in adjacent normal tissues (3.3%, 3/92). No MINT2 methylation was found in healthy controls, and partial MINT2 methylation was observed in three (6.25%, 3/48) patients with chronic atrophic gastritis. The frequency of MINT2 methylation in pairing PPLF and blood samples from 92 GC patients was 40.2% (37/92) and 39.1% (36/92), respectively. Methylated MINT2 in tumor tissues, pairing PPLF, and blood samples were very approximate. Aberrant MINT2 methylation in tumor tissues and pairing PPLF or blood samples were closely related to peritoneal dissemination, tumor progression, and poor prognosis (all P < 0.0001). CONCLUSIONS Aberrant MINT2 methylation in PPLF/blood may predict peritoneal micrometastasis for GC patients, which is a potential poor prognostic factor in GC.
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Berlth F, Bollschweiler E, Drebber U, Hoelscher AH, Moenig S. Pathohistological classification systems in gastric cancer: Diagnostic relevance and prognostic value. World J Gastroenterol 2014; 20:5679-5684. [PMID: 24914328 PMCID: PMC4024777 DOI: 10.3748/wjg.v20.i19.5679] [Citation(s) in RCA: 135] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 01/13/2014] [Accepted: 02/17/2014] [Indexed: 02/06/2023] Open
Abstract
Several pathohistological classification systems exist for the diagnosis of gastric cancer. Many studies have investigated the correlation between the pathohistological characteristics in gastric cancer and patient characteristics, disease specific criteria and overall outcome. It is still controversial as to which classification system imparts the most reliable information, and therefore, the choice of system may vary in clinical routine. In addition to the most common classification systems, such as the Laurén and the World Health Organization (WHO) classifications, other authors have tried to characterize and classify gastric cancer based on the microscopic morphology and in reference to the clinical outcome of the patients. In more than 50 years of systematic classification of the pathohistological characteristics of gastric cancer, there is no sole classification system that is consistently used worldwide in diagnostics and research. However, several national guidelines for the treatment of gastric cancer refer to the Laurén or the WHO classifications regarding therapeutic decision-making, which underlines the importance of a reliable classification system for gastric cancer. The latest results from gastric cancer studies indicate that it might be useful to integrate DNA- and RNA-based features of gastric cancer into the classification systems to establish prognostic relevance. This article reviews the diagnostic relevance and the prognostic value of different pathohistological classification systems in gastric cancer.
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Ling ZQ, Lv P, Lu XX, Yu JL, Han J, Ying LS, Zhu X, Zhu WY, Fang XH, Wang S, Wu YC. Circulating Methylated XAF1 DNA Indicates Poor Prognosis for Gastric Cancer. PLoS One 2013; 8:e67195. [PMID: 23826230 PMCID: PMC3695092 DOI: 10.1371/journal.pone.0067195] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2013] [Accepted: 05/16/2013] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Methylated DNA in fluids may be a suitable biomarker for cancer patients. XAF1 has been shown to be frequently down-regulated in human gastric cancer (GC). Here, we investigated if XAF1 methylation in GC could be a useful biomarker. METHODS Real-time RT-PCR was used to detect XAF1 mRNA expression; immunohistochemistry and western blot were used to examine XAF1 protein expression in GC tissues (n = 202) and their corresponding para-cancerous histological normal tissues (PCHNTs). Real-time methylation specific-PCR was used to investigate XAF1 promoter methylation in the same panel of GC tissues, their PCHNTs and sera. RESULTS We confirmed frequent XAF1 down-regulation in both mRNA and protein levels in GC tissues as compared to normal controls and PCHNTs. XAF1 hypermethylation was evidenced in 83.2% (168/202) of GC tissues and 27.2% (55/202) of PCHNTs, while no methylation was detected in the 88 normal controls. The methylation level in GC tissues was significantly higher than that in PCHNTs (p<0.05). The hypermethylation of XAF1 significantly correlated with the down-regulation of XAF1 in GC tissues in both mRNA and protein levels (p<0.001 each). Moreover, we detected high frequency of XAF1 methylation (69.8%, 141 out of 202) in the sera DNAs from the same patients, while the sera DNAs from 88 non-tumor controls were negative for XAF1 methylation. The XAF1 methylation in both GC tissues and in the sera could be a good biomarker for diagnosis of GC (AUC = 0.85 for tissue and AUC = 0.91 for sera) and significantly correlated with poorer prognosis (p<0.001). In addition, after-surgery negative-to-positive transition of XAF1 methylation in sera strongly associated with tumor recurrence. CONCLUSIONS 1) Dysfunction of XAF1 is frequent and is regulated through XAF1 promoter hypermethylation; 2) Detection of circulating methylated XAF1 DNAs in the serum may be a useful biomarker in diagnosis, evaluating patient's outcome (prognosis and recurrence) for GC patients.
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Affiliation(s)
- Zhi-Qiang Ling
- Zhejiang Cancer Research Institute, Zhejiang Province Cancer Hospital, Zhejiang Cancer Center, Hangzhou, Zhejiang, China
| | - Ping Lv
- Zhejiang Cancer Research Institute, Zhejiang Province Cancer Hospital, Zhejiang Cancer Center, Hangzhou, Zhejiang, China
| | - Xiao-Xiao Lu
- Zhejiang Cancer Research Institute, Zhejiang Province Cancer Hospital, Zhejiang Cancer Center, Hangzhou, Zhejiang, China
| | - Jiang-Liu Yu
- Zhejiang Cancer Research Institute, Zhejiang Province Cancer Hospital, Zhejiang Cancer Center, Hangzhou, Zhejiang, China
| | - Jing Han
- Zhejiang Cancer Research Institute, Zhejiang Province Cancer Hospital, Zhejiang Cancer Center, Hangzhou, Zhejiang, China
| | - Li-Sha Ying
- Zhejiang Cancer Research Institute, Zhejiang Province Cancer Hospital, Zhejiang Cancer Center, Hangzhou, Zhejiang, China
| | - Xin Zhu
- Zhejiang Cancer Research Institute, Zhejiang Province Cancer Hospital, Zhejiang Cancer Center, Hangzhou, Zhejiang, China
| | - Wang-Yu Zhu
- Zhejiang Cancer Research Institute, Zhejiang Province Cancer Hospital, Zhejiang Cancer Center, Hangzhou, Zhejiang, China
| | - Xian-Hua Fang
- Department of Pathology, Zhejiang Province Cancer Hospital, Zhejiang Cancer Center, Hangzhou, Zhejiang, China
| | - Shi Wang
- Department of Endoscopy, Zhejiang Province Cancer Hospital, Zhejiang Cancer Center, Hangzhou, Zhejiang, China
| | - Yi-Chen Wu
- Zhejiang Cancer Research Institute, Zhejiang Province Cancer Hospital, Zhejiang Cancer Center, Hangzhou, Zhejiang, China
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New invasive patterns as a prognostic factor for superficial esophageal cancer. J Gastroenterol 2012; 47:1279-89. [PMID: 22576024 DOI: 10.1007/s00535-012-0587-y] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2011] [Accepted: 03/23/2012] [Indexed: 02/04/2023]
Abstract
BACKGROUND Prognostic factors for superficial esophageal cancer cannot be limited to such factors as lymph node metastasis (N factor), depth of tumor invasion (T factor), and genetic alterations. The purpose of this study was to examine whether invasive growth patterns of tumors, such as infiltrative growth pattern c (INFc) and budding, represent new useful prognostic factors for superficial esophageal cancer. METHODS We investigated 87 cases of superficial esophageal cancer in patients treated with radical surgery. First, the invasive growth pattern of the tumor was pathologically evaluated based on the traditional infiltrative growth pattern (INF) classification. Next, new INF criteria were proposed, and the invasive pattern was re-evaluated. We also investigated budding (Bud) in the stroma of the invasive frontal lesion. RESULTS When the patients were divided into two groups, with and without an INFc component, the group with an INFc component had a poorer outcome than the group without an INFc component. When the group with an INFc component was defined as "new INFc", new INFc was correlated with the T factor (p = 0.006) and the ly factor (lymphatic invasion) (p = 0.041). Bud was correlated with the T factor (p = 0.001), the N factor (p = 0.030), and new INFc (p < 0.001). An analysis of survival revealed new INFc (p = 0.002) and Bud (p = 0.006) to be prognostic factors. The survival of the group with new INFc(+)/Bud(+) was poorer than that with new INFc(-)/Bud(-) (p = 0.007). CONCLUSIONS New INFc and Bud, which represent new invasive patterns, were prognostic factors for superficial esophageal cancer.
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Noda S, Yashiro M, Toyokawa T, Morimoto J, Shinto O, Muguruma K, Sawada T, Hirakawa K. Borrmann's macroscopic criteria and p-Smad2 expression are useful predictive prognostic markers for cytology-positive gastric cancer patients without overt peritoneal metastasis. Ann Surg Oncol 2011; 18:3718-25. [PMID: 21573834 DOI: 10.1245/s10434-011-1768-2] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2010] [Indexed: 12/21/2022]
Abstract
BACKGROUND All patients with peritoneal-free cancer cells (CY1) do not always develop a peritoneal recurrence (P1). The goal of this study was to identify characteristic features of peritoneal-free cancer cells that could develop into peritoneal recurrence. METHODS Of 1,474 patients, 91 were identified with CY1P0, and the remaining 1,383 with CY0P0. Immunohistochemical staining with anti-phosphorylated Smad 2 (p-Smad2) was performed on paraffin-embedded specimens from the 91 CY1P0 patients. RESULTS CY1 was significantly correlated with Borrmann's type-4 cancer, clinical T stage, and lymph node metastasis. CY1P0 patients with Borrmann's type-4 cancer more frequently develop peritoneal recurrence than do those with other types of tumors. The 5-year survival rate of patients with Borrmann's type-4 tumors was significantly (p = 0.023) low (6.3%) compared with that of patients with other types of tumors (27.7%). The prognosis for p-Smad2-positive patients was significantly poorer than that of p-Smad2-negative patients. In CY1 and/or P1 patients with Borrmann's type-4 tumors, no significant difference in prognosis was identified between those who had surgery and those who did not. CONCLUSIONS Activated Smad signaling might be associated with a high potential for peritoneal recurrence in CY1P0 patients. Borrmann's macroscopic criteria and p-Smad2 expression are useful markers for surgeons selecting advanced gastric cancer patients with CY1P0 for gastrectomy.
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Affiliation(s)
- Satoru Noda
- Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka, Japan
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Palliative gastrectomy and other factors affecting overall survival in stage IV gastric adenocarcinoma patients receiving chemotherapy: a retrospective analysis. Eur J Surg Oncol 2011; 37:312-8. [PMID: 21300519 DOI: 10.1016/j.ejso.2011.01.019] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2010] [Revised: 12/16/2010] [Accepted: 01/17/2011] [Indexed: 02/01/2023] Open
Abstract
OBJECTIVE Most patients with gastric cancer present with locally advanced or metastatic disease and usually receive palliative therapy. We sought to identify factors influencing overall survival in patients with stage IV gastric cancer receiving palliative chemotherapy. PATIENTS AND METHODS The records of 311 patients with histological diagnosis of gastric adenocarcinoma were retrospectively reviewed and 17 clinicopathological and therapeutic parameters were evaluated for their influence on overall survival. RESULTS In multivariate analysis nine factors were found to independently influence survival: no previous palliative gastrectomy [Hazard ratio (HR, 12; CI 7.969-18.099)], single agent chemotherapy instead of combination chemotherapy (HR, 1.35; CI 1.068-1.721), histological grade III (HR, 1.39; 95% CI 1.098-1.782), the presence of hepatic (HR, 1.6; 95% CI 1.246-2.073) and abdominal metastasis (HR, 1.33; 95% CI 1.039-1.715), CA 72-4 > 7 U/L (HR, 1.39; 95% CI 1.026-1.887), LDH > 225 U/L (HR, 1.72; 95% CI 1.336-2.236], need for blood transfusions (HR, 1.58; 95% CI 1.213-2.082), and weight loss > 5% (HR, 1.96; 95% CI 1.352-2.853) at the time of initial diagnosis. Patients were stratified as low (0-2 factors), intermediate (3-6 factors) and high (7-9 factors) risk and the median survival was 76, 40 and 11 weeks, respectively. CONCLUSION Nine clinical and laboratory factors that adversely affect survival in patients with stage IV gastric cancer who receive chemotherapy were identified. Their concurrent presence seems to have an additive effect as patients with seven to nine factors have the worse prognosis. Palliative gastrectomy and combination chemotherapy appear to be associated with improved survival.
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Barros-Silva JD, Leitão D, Afonso L, Vieira J, Dinis-Ribeiro M, Fragoso M, Bento MJ, Santos L, Ferreira P, Rêgo S, Brandão C, Carneiro F, Lopes C, Schmitt F, Teixeira MR. Association of ERBB2 gene status with histopathological parameters and disease-specific survival in gastric carcinoma patients. Br J Cancer 2009; 100:487-93. [PMID: 19156142 PMCID: PMC2658544 DOI: 10.1038/sj.bjc.6604885] [Citation(s) in RCA: 132] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
The clinical significance of ERBB2 amplification/overexpression in gastric cancer remains unclear. In this study, we evaluated the ERBB2 status in 463 gastric carcinomas using immunohistochemistry (IHC) and fluorescence in situ hybridisation (FISH), and compared the findings with histopathological characteristics and with disease-specific survival. ERBB2 overexpression (2+ and 3+) and amplification (ratio ERBB2/CEP17⩾2) were found in 43 (9.3%) and 38 (8.2%) gastric carcinomas, respectively. Perfect IHC/FISH correlation was found for the 19 cases scored as 0 (all negative by FISH), and also for the 25 cases scored as 3+ (all positive by FISH). One out of six carcinomas scored as 1+ and 12 out of 18 carcinomas scored as 2+ were positive by FISH. ERBB2 amplification was associated with gastric carcinomas of intestinal type (P=0.007) and with an expansive growth pattern (P=0.021). ERBB2 amplification was detected in both histological components of two mixed carcinomas, indicating a common clonal origin. A statistically significant association was found between ERBB2 amplification and worse survival in patients with expansive gastric carcinomas (P=0.011). We conclude that ERBB2 status may have clinical significance in subsets of gastric cancer patients, and that further studies are warranted to evaluate whether patients whose gastric carcinomas present ERBB2 amplification/overexpression may benefit from therapy targeting this surface receptor.
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Affiliation(s)
- J D Barros-Silva
- Department of Genetics, Portuguese Oncology Institute, Porto, Portugal
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Lu Y, Liu C, Zhang R, Li H, Lu P, Jin F, Xu H, Wang S, Chen J. Prognostic significance of subclassification of pT2 gastric cancer: a retrospective study of 847 patients. Surg Oncol 2008; 17:317-22. [PMID: 18586486 DOI: 10.1016/j.suronc.2008.05.005] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2008] [Revised: 04/09/2008] [Accepted: 05/19/2008] [Indexed: 12/23/2022]
Abstract
PURPOSE To investigate the prognostic significance of subclassification of pT2 gastric cancers according to the nodal status. METHODS Clinicopathological characteristics and prognostic outcomes of 847 gastric cancer patients who received a gastrectomy between 1985 and 2003 were retrospectively evaluated based on the subclassification of pT2 stage (i.e. pT2a and pT2b). RESULTS Of the patients, 244 and 603 had pT2a and pT2b stage cancers, respectively. Patients with pT2a cancers had a significantly longer disease-specific 5-year survival rate than those with pT2b cancers (P<0.001). The prognosis was significantly better in patients with pT2a cancers than in patients with pT2b cancers at pN0, pN1 and pN2 (P=0.036, 0.021, and 0.019 respectively), but not pN3 stages (P=0.775). Multivariate analysis identified age, tumor location, pT stages, pN stages, and adjuvant chemotherapy as independent prognostic factors for pT2 gastric cancers. The survival rates were similar between pT2aN1 (stage II) and pT2bN0 (stage IB) cancers (P=0.604), and between pT2aN2 (stage IIIA) and pT2bN1 (stage II) cancers (P=0.936). CONCLUSIONS Subclassification of pT2 gastric cancers into pT2a or pT2b is of prominent prognostic significance, and thus it is recommended that the current stage grouping conventions include subclassification of pT2, in order to more accurately predict the prognosis of patients.
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Affiliation(s)
- Yang Lu
- Department of Oncology, First Affiliated Hospital of China Medical University, Shenyang, China
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