|
1
|
In K, Kang S, Lee H, Eun H, Moon H, Lee E, Kim S, Sung J, Lee B. Proportional Correlation Between Systemic Inflammation Response Index and Gastric Cancer Recurrence Time: A Retrospective Study. Cancers (Basel) 2025; 17:1415. [PMID: 40361340 PMCID: PMC12070897 DOI: 10.3390/cancers17091415] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2025] [Revised: 04/17/2025] [Accepted: 04/21/2025] [Indexed: 05/15/2025] Open
Abstract
BACKGROUND Disease recurrence is the primary cause of death in patients with gastric cancer who have undergone complete surgical resection. No prognostic factors for recurrence, other than the Tumor, Node, and Metastasis stage, have been established. However, recurrence rates differ even within the same Tumor, Node, and Metastasis stage. Therefore, we aimed to develop a new prognostic confidence measure for gastric cancer recurrence and demonstrate its practical utility. METHODS This was a retrospective study based on the medical records of the Chungnam National University Hospital, Republic of Korea. We enrolled patients diagnosed with stage II/III gastric cancer who underwent complete surgical resection and adjuvant chemotherapy over the past 12 years. The association between seven variables, including the systemic inflammation response index (SIRI) and gastric cancer recurrence, was analyzed. RESULTS A total of 296 patients were enrolled in this study. Although other factors did not exhibit significant correlations, SIRI showed a significant positive correlation with gastric cancer recurrence risk, confirmed through Cox regression testing (hazard ratio, 1.231; 95% confidence interval, 1.04-1.45). Linear regression analysis revealed a significant association between higher SIRI values and shorter recurrence time (p = 0.044; β = -0.225). CONCLUSIONS In this study, other than SIRI, effective prognostic factors related to gastric cancer recurrence were not verified, thus indicating SIRI as a potential independent prognostic factor.
Collapse
Affiliation(s)
| | - Sunhyung Kang
- Division of Gastroenterology, Department of Internal Medicine, Chungnam National University Hospital, Chungnam National University School of Medicine, Daejeon 35015, Republic of Korea; (K.I.); (H.L.); (H.E.); (H.M.); (E.L.); (S.K.); (J.S.); (B.L.)
| | | | | | | | | | | | | | | |
Collapse
|
|
2
|
Seo T, Lowery AM, Xu H, Giang W, Troyanovsky SM, Vincent PA, Kowalczyk AP. MARCH family E3 ubiquitin ligases selectively target and degrade cadherin family proteins. PLoS One 2024; 19:e0290485. [PMID: 38722959 PMCID: PMC11081302 DOI: 10.1371/journal.pone.0290485] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Accepted: 04/19/2024] [Indexed: 05/13/2024] Open
Abstract
Cadherin family proteins play a central role in epithelial and endothelial cell-cell adhesion. The dynamic regulation of cell adhesion is achieved in part through endocytic membrane trafficking pathways that modulate cadherin cell surface levels. Here, we define the role for various MARCH family ubiquitin ligases in the regulation of cadherin degradation. We find that MARCH2 selectively downregulates VE-cadherin, resulting in loss of adherens junction proteins at cell borders and a loss of endothelial barrier function. Interestingly, N-cadherin is refractory to MARCH ligase expression, demonstrating that different classical cadherin family proteins are differentially regulated by MARCH family ligases. Using chimeric cadherins, we find that the specificity of different MARCH family ligases for different cadherins is conferred by the cadherin transmembrane domain. Further, juxta-membrane lysine residues are required for cadherin degradation by MARCH proteins. These findings expand our understanding of cadherin regulation and highlight a new role for mammalian MARCH family ubiquitin ligases in differentially regulating cadherin turnover.
Collapse
Affiliation(s)
- Tadahiko Seo
- Departments of Dermatology and Cellular and Molecular Physiology, College of Medicine, Pennsylvania State University, Hershey, Pennsylvania, United States of America
| | - Anthony M. Lowery
- Department of Molecular and Cellular Physiology, Albany Medical College, Albany, New York, United States of America
| | - Haifang Xu
- Departments of Dermatology and Cellular and Molecular Physiology, College of Medicine, Pennsylvania State University, Hershey, Pennsylvania, United States of America
| | - William Giang
- Departments of Dermatology and Cellular and Molecular Physiology, College of Medicine, Pennsylvania State University, Hershey, Pennsylvania, United States of America
| | - Sergey M. Troyanovsky
- Department of Dermatology, The Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America
- Department of Cell and Developmental Biology, The Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America
| | - Peter A. Vincent
- Department of Molecular and Cellular Physiology, Albany Medical College, Albany, New York, United States of America
| | - Andrew P. Kowalczyk
- Departments of Dermatology and Cellular and Molecular Physiology, College of Medicine, Pennsylvania State University, Hershey, Pennsylvania, United States of America
| |
Collapse
|
|
3
|
Seo T, Lowery AM, Xu H, Giang W, Troyanovsky SM, Vincent PA, Kowalczyk AP. MARCH family E3 ubiquitin ligases selectively target and degrade cadherin family proteins. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.08.10.552739. [PMID: 37609155 PMCID: PMC10441400 DOI: 10.1101/2023.08.10.552739] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/24/2023]
Abstract
Cadherin family proteins play a central role in epithelial and endothelial cell-cell adhesion. The dynamic regulation of cell adhesion is achieved in part through endocytic membrane trafficking pathways that modulate cadherin cell surface levels. Here, we define the role for various MARCH family ubiquitin ligases in the regulation of cadherin degradation. We find that MARCH2 selectively downregulates VE-cadherin, resulting in loss of adherens junction proteins at cell borders and a loss of endothelial barrier function. Interestingly, N-cadherin is refractory to MARCH ligase expression, demonstrating that different classical cadherin family proteins are differentially regulated by MARCH family ligases. Using chimeric cadherins, we find that the specificity of different MARCH family ligases for different cadherins is conferred by the cadherin transmembrane domain. Further, juxta-membrane lysine residues are required for cadherin degradation by MARCH proteins. These findings expand our understanding of cadherin regulation and highlight a new role for mammalian MARCH family ubiquitin ligases in differentially regulating cadherin turnover.
Collapse
Affiliation(s)
- Tadahiko Seo
- Departments of Dermatology and Cellular and Molecular Physiology, Pennsylvania State College of Medicine, Hershey, Pennsylvania, United States of America
| | - Anthony M. Lowery
- Department of Molecular and Cellular Physiology, Albany Medical College, Albany, New York, United States of America
| | - Haifang Xu
- Departments of Dermatology and Cellular and Molecular Physiology, Pennsylvania State College of Medicine, Hershey, Pennsylvania, United States of America
| | - William Giang
- Departments of Dermatology and Cellular and Molecular Physiology, Pennsylvania State College of Medicine, Hershey, Pennsylvania, United States of America
| | - Sergey M. Troyanovsky
- Department of Dermatology, The Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America
- Department of Cell and Developmental Biology, The Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America
| | - Peter A. Vincent
- Department of Molecular and Cellular Physiology, Albany Medical College, Albany, New York, United States of America
| | - Andrew P. Kowalczyk
- Departments of Dermatology and Cellular and Molecular Physiology, Pennsylvania State College of Medicine, Hershey, Pennsylvania, United States of America
| |
Collapse
|
|
4
|
Bernegger S, Jarzab M, Wessler S, Posselt G. Proteolytic Landscapes in Gastric Pathology and Cancerogenesis. Int J Mol Sci 2022; 23:2419. [PMID: 35269560 PMCID: PMC8910283 DOI: 10.3390/ijms23052419] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 02/17/2022] [Accepted: 02/18/2022] [Indexed: 02/01/2023] Open
Abstract
Gastric cancer is a leading cause of cancer-related death, and a large proportion of cases are inseparably linked to infections with the bacterial pathogen and type I carcinogen Helicobacter pylori. The development of gastric cancer follows a cascade of transformative tissue events in an inflammatory environment. Proteases of host origin as well as H. pylori-derived proteases contribute to disease progression at every stage, from chronic gastritis to gastric cancer. In the present article, we discuss the importance of (metallo-)proteases in colonization, epithelial inflammation, and barrier disruption in tissue transformation, deregulation of cell proliferation and cell death, as well as tumor metastasis and neoangiogenesis. Proteases of the matrix metalloproteinase (MMP) and a disintegrin and metalloproteinase domain-containing protein (ADAM) families, caspases, calpain, and the H. pylori proteases HtrA, Hp1012, and Hp0169 cleave substrates including extracellular matrix molecules, chemokines, and cytokines, as well as their cognate receptors, and thus shape the pathogenic microenvironment. This review aims to summarize the current understanding of how proteases contribute to disease progression in the gastric compartment.
Collapse
Affiliation(s)
- Sabine Bernegger
- Division of Microbiology, Department of Biosciences and Medical Biology, Paris Lodron University of Salzburg, Hellbrunner Strasse 34, 5020 Salzburg, Austria; (S.B.); (M.J.); (S.W.)
| | - Miroslaw Jarzab
- Division of Microbiology, Department of Biosciences and Medical Biology, Paris Lodron University of Salzburg, Hellbrunner Strasse 34, 5020 Salzburg, Austria; (S.B.); (M.J.); (S.W.)
| | - Silja Wessler
- Division of Microbiology, Department of Biosciences and Medical Biology, Paris Lodron University of Salzburg, Hellbrunner Strasse 34, 5020 Salzburg, Austria; (S.B.); (M.J.); (S.W.)
- Cancer Cluster Salzburg and Allergy Cancer BioNano Research Centre, University of Salzburg, Hellbrunner Strasse 34, 5020 Salzburg, Austria
| | - Gernot Posselt
- Division of Microbiology, Department of Biosciences and Medical Biology, Paris Lodron University of Salzburg, Hellbrunner Strasse 34, 5020 Salzburg, Austria; (S.B.); (M.J.); (S.W.)
| |
Collapse
|
|
5
|
Reproduction of the Cancer Genome Atlas (TCGA) and Asian Cancer Research Group (ACRG) Gastric Cancer Molecular Classifications and Their Association with Clinicopathological Characteristics and Overall Survival in Moroccan Patients. DISEASE MARKERS 2021; 2021:9980410. [PMID: 34367379 PMCID: PMC8342151 DOI: 10.1155/2021/9980410] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 07/07/2021] [Accepted: 07/09/2021] [Indexed: 12/13/2022]
Abstract
Introduction The Cancer Genome Atlas (TCGA) project and Asian Cancer Research Group (ACRG) recently categorized gastric cancer into molecular subtypes. Nevertheless, these classification systems require high cost and sophisticated molecular technologies, preventing their widespread use in the clinic. This study is aimed to generating molecular subtypes of gastric cancer using techniques available in routine diagnostic practice in a series of Moroccan gastric cancer patients. In addition, we assessed the associations between molecular subtypes, clinicopathological features, and prognosis. Methods Ninety-seven gastric cancer cases were classified according to TCGA, ACRG, and integrated classifications using a panel of four molecular markers (EBV, MSI, E-cadherin, and p53). HER2 status and PD-L1 expression were also evaluated. These markers were analyzed using immunohistochemistry (E-cadherin, p53, HER2, and PD-L1), in situ hybridization (EBV and HER2 equivocal cases), and multiplex PCR (MSI). Results Our results showed that the subtypes presented distinct clinicopathological features and prognosis. EBV-positive gastric cancers were found exclusively in male patients. The GS (TCGA classification), MSS/EMT (ACRG classification), and E-cadherin aberrant subtype (integrated classification) presented the Lauren diffuse histology enrichment and tended to be diagnosed at a younger age. The MSI subtype was associated with a better overall survival across all classifications (TCGA, ACRG, and integrated classification). The worst prognosis was observed in the EBV subtype (TCGA and integrated classification) and MSS/EMT subtype (ACRG classification). Discussion/Conclusion. We reported a reproducible and affordable gastric cancer subtyping algorithms that can reproduce the recently recognized TCGA, ACRG, and integrated gastric cancer classifications, using techniques available in routine diagnosis. These simplified classifications can be employed not only for molecular classification but also in predicting the prognosis of gastric cancer patients.
Collapse
|
|
6
|
Wu J, Han J, Zhang Y, Liang L, Zhao J, Han F, Dou C, Zhang Y, Liu J, Wu W, Hu Z, Zhang C. Safety and feasibility of laparoscopic versus open liver resection with associated lymphadenectomy for intrahepatic cholangiocarcinoma. Biosci Trends 2020; 14:376-383. [PMID: 32921695 DOI: 10.5582/bst.2020.03293] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The safety and feasibility of laparoscopic versus open liver resection (LLR vs. OLR) associated lymphadenectomy for intrahepatic cholangiocarcinoma (ICC) are still controversial. The aim of the present study was to compare short and long-term outcomes. We reviewed data on 43 consecutive patients who underwent curative liver resection with associated lymphadenectomy for ICC. The short-term outcomes including postoperative morbidity and mortality, and the long-term outcomes including overall survival (OS) and recurrence-free survival (RFS) were compared. The median survival, 1- and 3-year OS in LLR and OLR groups were 22.5 months, 76.9% and 47.1%, and 12.1 months, 43.1% and 20.0%, respectively. The median survival, 1- and 3-year RFS in LLR and OLR groups were 10.3 months, 27.8% and 0%, and 8.1 months, 24.0% and 4.0%, respectively. The results showed that LLR obviously reduced intraoperative blood loss (median, 375 vs. 500ml, p = 0.016) and postoperative hospital stay (median, 6 vs. 9 days, p = 0.016). Moreover, there was no significant difference in short-term outcomes including postoperative morbidity (including wound infection, bile leakage, liver failure and pneumonia) and mortality within 30 days, and long-term outcomes including OS and RFS between LLR and OLR. (all p > 0.05). Multivariate analysis showed that CA19-9 level, TNM stage, and tumor differentiation were independent risk factors for OS and RFS. LLR for ICC is safety and feasibility compared with OLR. The advantage of LLR was to reduce intraoperative blood loss and postoperative hospital stay.
Collapse
Affiliation(s)
- Jia Wu
- Department of Hepatobiliary and Pancreatic Surgery & Minimally Invasive Surgery, Zhejiang Provincial People's Hospital & Hangzhou Medical College affiliated People's Hospital, Hangzhou, Zhejiang, China
| | - Junjun Han
- Graduate Department, Bengbu Medical College, Bengbu, Anhui, China
| | - Yuhua Zhang
- Department of Hepatobiliary and Pancreatic Surgery & Minimally Invasive Surgery, Zhejiang Provincial People's Hospital & Hangzhou Medical College affiliated People's Hospital, Hangzhou, Zhejiang, China
| | - Lei Liang
- Department of Hepatobiliary and Pancreatic Surgery & Minimally Invasive Surgery, Zhejiang Provincial People's Hospital & Hangzhou Medical College affiliated People's Hospital, Hangzhou, Zhejiang, China
| | - Junjun Zhao
- Graduate Department, Bengbu Medical College, Bengbu, Anhui, China
| | - Fang Han
- Department of Hepatobiliary and Pancreatic Surgery & Minimally Invasive Surgery, Zhejiang Provincial People's Hospital & Hangzhou Medical College affiliated People's Hospital, Hangzhou, Zhejiang, China
| | - Changwei Dou
- Department of Hepatobiliary and Pancreatic Surgery & Minimally Invasive Surgery, Zhejiang Provincial People's Hospital & Hangzhou Medical College affiliated People's Hospital, Hangzhou, Zhejiang, China
| | - Yuanbiao Zhang
- Department of Hepatobiliary and Pancreatic Surgery & Minimally Invasive Surgery, Zhejiang Provincial People's Hospital & Hangzhou Medical College affiliated People's Hospital, Hangzhou, Zhejiang, China
| | - Jie Liu
- Department of Hepatobiliary and Pancreatic Surgery & Minimally Invasive Surgery, Zhejiang Provincial People's Hospital & Hangzhou Medical College affiliated People's Hospital, Hangzhou, Zhejiang, China
| | - Weiding Wu
- Department of Hepatobiliary and Pancreatic Surgery & Minimally Invasive Surgery, Zhejiang Provincial People's Hospital & Hangzhou Medical College affiliated People's Hospital, Hangzhou, Zhejiang, China
| | - Zhiming Hu
- Department of Hepatobiliary and Pancreatic Surgery & Minimally Invasive Surgery, Zhejiang Provincial People's Hospital & Hangzhou Medical College affiliated People's Hospital, Hangzhou, Zhejiang, China
| | - Chengwu Zhang
- Department of Hepatobiliary and Pancreatic Surgery & Minimally Invasive Surgery, Zhejiang Provincial People's Hospital & Hangzhou Medical College affiliated People's Hospital, Hangzhou, Zhejiang, China
| |
Collapse
|
|
7
|
Di Pinto F, Armentano R, Arborea G, Schena N, Donghia R, Valentini AM. Are Immunohistochemical Markers Useful in Phenotypic Gastric Cancer Classification? Oncology 2020; 98:566-574. [PMID: 32316005 DOI: 10.1159/000506077] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Accepted: 01/21/2020] [Indexed: 11/19/2022]
Abstract
To identify useful markers for prognostic and therapeutic purposes, The Cancer Genome Atlas (TCGA) provided a molecular classification of gastric cancers (GCs). Previous studies have used immunohistochemistry (IHC) and chromogenic in situ hybridization (CISH) to define immunophenotypic surrogate markers of the molecular alterations. Some critical issues concerning the correct definition of immunophenotypic groups have emerged in these studies that employed tissue microarrays (TMAs). We performed an immunophenotypic classification by evaluating MLH1, p53, HER2, E-cadherin, and Epstein-Barr virus (EBV) on the whole section of the surgical GC samples compared to most of the studies conducted on TMAs. We also investigated the immunohistochemical expression of PD-L1, a known therapeutic target. We identified the following immunophenotypic groups: EBV (2.9%); mismatch repair deficient (MMR-D) (7.2%); overexpressed p53 and/or HER2+ (61.4%); aberrant E-cadherin (11.4%); and normal pattern (17.1%). The use of surgical samples emphasized that some immunohistochemical markers were not useful for properly classifying the GC specimens. We can state that EBV (significantly correlated to PD-L1 expression) and MMR-D GCs are well-defined groups, mutually exclusive, and easily assessable with IHC and CISH, and could be candidates for immunotherapy with PD-1/PD-L1 inhibitors. As regards p53, our findings suggest that IHC assessment may be responsible for a misclassification of GC groups. Immunohistochemical evaluation of E-cadherin needs to be standardized, particularly in terms of the heterogeneous cytoplasmic/membranous staining pattern. Whether to consider the normal-pattern group as a separate category remains to be clarified. Because GC specimens with known therapeutic targets account for only 40%, we suggest reviewing the immunophenotypic classification to find new therapeutic targets, such as PD-L1, MLH1, and HER2.
Collapse
Affiliation(s)
- Federica Di Pinto
- Department of Pathology, National Institute of Gastroenterology "S. de Bellis," Research Hospital, Castellana Grotte, Bari, Italy
| | - Raffaele Armentano
- Department of Pathology, National Institute of Gastroenterology "S. de Bellis," Research Hospital, Castellana Grotte, Bari, Italy
| | - Graziana Arborea
- Department of Pathology, National Institute of Gastroenterology "S. de Bellis," Research Hospital, Castellana Grotte, Bari, Italy
| | - Nicolò Schena
- Department of Pathology, National Institute of Gastroenterology "S. de Bellis," Research Hospital, Castellana Grotte, Bari, Italy
| | - Rossella Donghia
- Unit of Epidemiological Research on Frailty Phenotype, National Institute of Gastroenterology "S. de Bellis," Research Hospital, Castellana Grotte, Bari, Italy
| | - Anna Maria Valentini
- Department of Pathology, National Institute of Gastroenterology "S. de Bellis," Research Hospital, Castellana Grotte, Bari, Italy,
| |
Collapse
|
|
8
|
Cho SY, Park JW, Liu Y, Park YS, Kim JH, Yang H, Um H, Ko WR, Lee BI, Kwon SY, Ryu SW, Kwon CH, Park DY, Lee JH, Lee SI, Song KS, Hur H, Han SU, Chang H, Kim SJ, Kim BS, Yook JH, Yoo MW, Kim BS, Lee IS, Kook MC, Thiessen N, He A, Stewart C, Dunford A, Kim J, Shih J, Saksena G, Cherniack AD, Schumacher S, Weiner AT, Rosenberg M, Getz G, Yang EG, Ryu MH, Bass AJ, Kim HK. Sporadic Early-Onset Diffuse Gastric Cancers Have High Frequency of Somatic CDH1 Alterations, but Low Frequency of Somatic RHOA Mutations Compared With Late-Onset Cancers. Gastroenterology 2017; 153:536-549.e26. [PMID: 28522256 PMCID: PMC6863080 DOI: 10.1053/j.gastro.2017.05.012] [Citation(s) in RCA: 92] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2016] [Revised: 05/08/2017] [Accepted: 05/08/2017] [Indexed: 12/19/2022]
Abstract
BACKGROUND & AIMS Early-onset gastric cancer, which develops in patients younger than most gastric cancers, is usually detected at advanced stages, has diffuse histologic features, and occurs more frequently in women. We investigated somatic genomic alterations associated with the unique characteristics of sporadic diffuse gastric cancers (DGCs) from younger patients. METHODS We conducted whole exome and RNA sequence analyses of 80 resected DGC samples from patients 45 years old or younger in Korea. Patients with pathogenic germline mutations in CDH1, TP53, and ATM were excluded from the onset of this analysis, given our focus on somatic alterations. We used MutSig2CV to evaluate the significance of mutated genes. We recruited 29 additional early-onset Korean DGC samples and performed SNP6.0 array and targeted sequencing analyses of these 109 early-onset DGC samples (54.1% female, median age, 38 years). We compared the SNP6.0 array and targeted sequencing data of the 109 early-onset DGC samples with those from diffuse-type stomach tumor samples collected from 115 patients in Korea who were 46 years or older (late onset) at the time of diagnosis (controls; 29.6% female, median age, 67 years). We compared patient survival times among tumors from different subgroups and with different somatic mutations. We performed gene silencing of RHOA or CDH1 in DGC cells with small interfering RNAs for cell-based assays. RESULTS We identified somatic mutations in the following genes in a significant number of early-onset DGCs: the cadherin 1 gene (CDH1), TP53, ARID1A, KRAS, PIK3CA, ERBB3, TGFBR1, FBXW7, RHOA, and MAP2K1. None of 109 early-onset DGC cases had pathogenic germline CDH1 mutations. A higher proportion of early-onset DGCs had mutations in CDH1 (42.2%) or TGFBR1 (7.3%) compared with control DGCs (17.4% and 0.9%, respectively) (P < .001 and P = .014 for CDH1 and TGFBR1, respectively). In contrast, a smaller proportion of early-onset DGCs contained mutations in RHOA (9.2%) than control DGCs (19.1%) (P = .033). Late-onset DGCs in The Cancer Genome Atlas also contained less frequent mutations in CDH1 and TGFBR1 and more frequent RHOA mutations, compared with early-onset DGCs. Early-onset DGCs from women contained significantly more mutations in CDH1 or TGFBR1 than early-onset DGCs from men. CDH1 alterations, but not RHOA mutations, were associated with shorter survival times in patients with early-onset DGCs (hazard ratio, 3.4; 95% confidence interval, 1.5-7.7). RHOA activity was reduced by an R5W substitution-the RHOA mutation most frequently detected in early-onset DGCs. Silencing of CDH1, but not RHOA, increased migratory activity of DGC cells. CONCLUSIONS In an integrative genomic analysis, we found higher proportions of early-onset DGCs to contain somatic mutations in CDH1 or TGFBR1 compared with late-onset DGCs. However, a smaller proportion of early-onset DGCs contained somatic mutations in RHOA than late-onset DGCs. CDH1 alterations, but not RHOA mutations, were associated with shorter survival times of patients, which might account for the aggressive clinical course of early-onset gastric cancer. Female predominance in early-onset gastric cancer may be related to relatively high rates of somatic CDH1 and TGFBR1 mutations in this population.
Collapse
Affiliation(s)
- Soo Young Cho
- National Cancer Center, Goyang, Gyeonggi, Republic of Korea
| | - Jun Won Park
- National Cancer Center, Goyang, Gyeonggi, Republic of Korea
| | - Yang Liu
- Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts
| | - Young Soo Park
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Ju Hee Kim
- National Cancer Center, Goyang, Gyeonggi, Republic of Korea
| | - Hanna Yang
- National Cancer Center, Goyang, Gyeonggi, Republic of Korea
| | - Hyejin Um
- National Cancer Center, Goyang, Gyeonggi, Republic of Korea
| | - Woo Ri Ko
- National Cancer Center, Goyang, Gyeonggi, Republic of Korea
| | - Byung Il Lee
- National Cancer Center, Goyang, Gyeonggi, Republic of Korea
| | - Sun Young Kwon
- Department of Pathology, Keimyung University School of Medicine, Daegu, Republic of Korea
| | - Seung Wan Ryu
- Department of Surgery, Keimyung University School of Medicine, Daegu, Republic of Korea
| | - Chae Hwa Kwon
- Department of Pathology and BioMedical Research Institute, Pusan National University Hospital and Pusan National University School of Medicine, Busan, Republic of Korea
| | - Do Youn Park
- Department of Pathology and BioMedical Research Institute, Pusan National University Hospital and Pusan National University School of Medicine, Busan, Republic of Korea
| | - Jae-Hyuk Lee
- Department of Pathology, Chonnam National University Medical School, Gwangju, Republic of Korea
| | - Sang Il Lee
- Department of Surgery, School of Medicine, Chungnam National University, Daejeon, Republic of Korea
| | - Kyu Sang Song
- Department of Pathology, School of Medicine, Chungnam National University, Daejeon, Republic of Korea
| | - Hoon Hur
- Department of Surgery, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Sang-Uk Han
- Department of Surgery, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Heekyung Chang
- Department of Pathology, Kosin University College of Medicine, Busan, Republic of Korea
| | - Su-Jin Kim
- Department of Pathology, Dong-A University College of Medicine, Busan, Republic of Korea
| | - Byung-Sik Kim
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jeong-Hwan Yook
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Moon-Won Yoo
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Beom-Su Kim
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - In-Seob Lee
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | | | - Nina Thiessen
- British Columbia Cancer Agency, Vancouver, British Columbia, Canada
| | - An He
- British Columbia Cancer Agency, Vancouver, British Columbia, Canada
| | - Chip Stewart
- Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts
| | - Andrew Dunford
- Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts
| | - Jaegil Kim
- Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts
| | - Juliann Shih
- Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Gordon Saksena
- Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts
| | - Andrew D Cherniack
- Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Steven Schumacher
- Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts
| | - Amaro-Taylor Weiner
- Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts
| | - Mara Rosenberg
- Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts
| | - Gad Getz
- Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts
| | - Eun Gyeong Yang
- Korea Institute of Science and Technology, Seoul, Republic of Korea
| | - Min-Hee Ryu
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Adam J Bass
- Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
| | - Hark Kyun Kim
- National Cancer Center, Goyang, Gyeonggi, Republic of Korea; National Cancer Center Graduate School of Cancer Science and Policy, Goyang, Gyeonggi, Republic of Korea.
| |
Collapse
|
|
9
|
A protein and mRNA expression-based classification of gastric cancer. Mod Pathol 2016; 29:772-84. [PMID: 27032689 DOI: 10.1038/modpathol.2016.55] [Citation(s) in RCA: 121] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2015] [Revised: 02/09/2016] [Accepted: 02/10/2016] [Indexed: 12/14/2022]
Abstract
The overall survival of gastric carcinoma patients remains poor despite improved control over known risk factors and surveillance. This highlights the need for new classifications, driven towards identification of potential therapeutic targets. Using sophisticated molecular technologies and analysis, three groups recently provided genetic and epigenetic molecular classifications of gastric cancer (The Cancer Genome Atlas, 'Singapore-Duke' study, and Asian Cancer Research Group). Suggested by these classifications, here, we examined the expression of 14 biomarkers in a cohort of 146 gastric adenocarcinomas and performed unsupervised hierarchical clustering analysis using less expensive and widely available immunohistochemistry and in situ hybridization. Ultimately, we identified five groups of gastric cancers based on Epstein-Barr virus (EBV) positivity, microsatellite instability, aberrant E-cadherin, and p53 expression; the remaining cases constituted a group characterized by normal p53 expression. In addition, the five categories correspond to the reported molecular subgroups by virtue of clinicopathologic features. Furthermore, evaluation between these clusters and survival using the Cox proportional hazards model showed a trend for superior survival in the EBV and microsatellite-instable related adenocarcinomas. In conclusion, we offer as a proposal a simplified algorithm that is able to reproduce the recently proposed molecular subgroups of gastric adenocarcinoma, using immunohistochemical and in situ hybridization techniques.
Collapse
|
|
10
|
Wang YW, Zhu ML, Wang RF, Xue WJ, Zhu XR, Wang LF, Zheng LZ. Predictable factors for lymph node metastasis in early gastric cancer analysis of clinicopathologic factors and biological markers. Tumour Biol 2016; 37:8567-78. [PMID: 26733174 DOI: 10.1007/s13277-015-4721-3] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2015] [Accepted: 12/21/2015] [Indexed: 12/29/2022] Open
Abstract
Predicting lymph node metastasis (LNM) accurately is very important to decide treatment strategies preoperatively. The aim of this study was to explore risk factors that predict the presence of LNM in early gastric cancer (EGC). A total of 230 patients with EGC who underwent curative gastrectomy with lymph adenectomy at Xinhua Hospital from January 2006 to July 2014 were retrospectively reviewed. We studied the relationship between clinicopathological factors, biological markers (p53, ki67, nm23, vascular endothelial growth factor (VEGF), epidermal growth factor receptor (EGFR), E-cadherin (E-cad), beta-catenin (b-catenin), glutathione S-transferase (GST), and topoisomerase II (Topo II)), and LNM of EGC patients by chi-square test and logistic regression analysis. Meta-analyses were further conducted to review the effects of the proteins (P53, ki67, E-cad, and b-catenin) on LNM in ECG patients. LNM was detected in 42 (18.3 %) of 230 patients. Incidences of LNM was distinct in different tumor size (p = 0.044), depth of submucosal invasion (p < 0.0001), and P53 overexpression (p = 0.004). Multivariate analysis further indentified that large tumor size (≥20 mm, odds ratio (OR) = 2.168, p = 0.041), submucosa (OR = 4.000, p = 0.0005), and P53 overexpression (OR = 3.010, p = 0.022) were independent risk factors of LNM in EGC patients. The meta-analysis revealed a significantly statistical association of P53, ki67, and b-catenin with an increased risk of LNM in EGC patients (P53, OR = 1.81, p = 0.017; ki67, OR = 2.53, p = 0.0003; b-catenin, OR = 0.53, p = 0.01). Tumor size (≥20 mm), the depth of invasion (submucosa), and P53 overexpression may be helpful predictors of LNM in EGC patients. Furthermore, the results of meta-analysis revealed that P53, ki67 overexpression, and abnormal expression of b-catenin may be associated with LNM in EGC. The results need further validation in single large studies.
Collapse
Affiliation(s)
- Yi-Wei Wang
- Department of Oncology, Xin Hua Hospital affiliated to Shanghai Jiaotong University School of Medicine, NO.1665, Kong Jiang Road, Shanghai, 200092, People's Republic of China
| | - Mei-Ling Zhu
- Department of Oncology, Xin Hua Hospital affiliated to Shanghai Jiaotong University School of Medicine, NO.1665, Kong Jiang Road, Shanghai, 200092, People's Republic of China
| | - Rui-Fen Wang
- Department of Pathology, Xin Hua Hospital affiliated to Shanghai Jiaotong University School of Medicine, NO.1665, Kong Jiang Road, Shanghai, 200092, People's Republic of China
| | - Wen-Ji Xue
- Department of Oncology, Xin Hua Hospital affiliated to Shanghai Jiaotong University School of Medicine, NO.1665, Kong Jiang Road, Shanghai, 200092, People's Republic of China
| | - Xue-Ru Zhu
- Department of Oncology, Xin Hua Hospital affiliated to Shanghai Jiaotong University School of Medicine, NO.1665, Kong Jiang Road, Shanghai, 200092, People's Republic of China
| | - Li-Feng Wang
- Department of Pathology, Xin Hua Hospital affiliated to Shanghai Jiaotong University School of Medicine, NO.1665, Kong Jiang Road, Shanghai, 200092, People's Republic of China.
| | - Lei-Zhen Zheng
- Department of Oncology, Xin Hua Hospital affiliated to Shanghai Jiaotong University School of Medicine, NO.1665, Kong Jiang Road, Shanghai, 200092, People's Republic of China.
| |
Collapse
|
|
11
|
Waldum HL, Hauso Ø, Sørdal ØF, Fossmark R. Gastrin May Mediate the Carcinogenic Effect of Helicobacter pylori Infection of the Stomach. Dig Dis Sci 2015; 60:1522-7. [PMID: 25480404 DOI: 10.1007/s10620-014-3468-9] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2014] [Accepted: 11/26/2014] [Indexed: 12/14/2022]
Abstract
Gastric cancer occurs almost exclusively in patients with gastritis. Since Helicobacter pylori (Hp) was proved to cause gastritis, Hp was also expected to play a role in gastric carcinogenesis. Despite extensive studies, the mechanisms by which Hp cause gastric cancer are still poorly understood. However, there is evidence that the anatomical site of Hp infection is of major importance. Infection confined to the antral mucosa protects against gastric cancer but predisposes to duodenal ulcer, whereas Hp infection of the oxyntic mucosa increases the risk of gastric cancer. Hp infection does not predispose to cancers in the gastric cardia. In patients with atrophic gastritis of the oxyntic mucosa, the intragastric pH is elevated and the concentration of microorganisms in the stomach is increased. This does not lead to increased risk of gastric cancer at all anatomical sites. The site specificity of Hp infection in relation to cancer risk indicates that neither Hp nor the changes in gastric microflora due to gastric hypoacidity are carcinogenic per se. However, reduced gastric acidity also leads to hypergastrinemia, which stimulates the function and proliferation of enterochromaffin-like (ECL) cells located in the oxyntic mucosa. The ECL cell may be more important in human gastric carcinogenesis than previously realized, as every condition causing long-term hypergastrinemia in animals results in the development of neoplasia in the oxyntic mucosa. Patients with hypergastrinemia will far more often develop carcinomas in the gastric corpus. In conclusion, hypergastrinemia may explain the carcinogenic effect of Hp.
Collapse
Affiliation(s)
- Helge L Waldum
- Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology, Prinsesse Kristinas Gate 1, 7006, Trondheim, Norway,
| | | | | | | |
Collapse
|
|
12
|
Waldum HL, Ringnes E, Nordbø H, Sørdal Ø, Nordrum IS, Hauso Ø. The normal neuroendocrine cells of the upper gastrointestinal tract lack E-cadherin. Scand J Gastroenterol 2014; 49:974-8. [PMID: 24742175 DOI: 10.3109/00365521.2014.909275] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE E-cadherin plays a crucial role in the adhesion between epithelial cells and thus epithelial integrity. Moreover, germline mutations in the E-cadherin gene (CDH1) causing loss of E-cadherin function (adhesion) leads to hereditary gastric cancer of the diffuse type, according to Laurén. Even sporadic gastric carcinomas of the diffuse type often lose E-cadherin expression due to mutations. Lack of E-cadherin has been recorded at an early phase in such carcinomas. For 25 years, we have provided evidence for neuroendocrine (NE) cell origin of gastric carcinomas of diffuse type. The present study was, therefore, done to examine whether normal NE cells in the gastrointestinal tract express E-cadherin or not. METHODS During upper gastrointestinal endoscopy, biopsies were taken from normal oxyntic mucosa, gastric carcinoids, gastric carcinomas, and from normal duodenal mucosa. Tissues were examined by immunohistochemistry (IHC) using antibodies toward chromogranin A, synaptophysin, and E-cadherin. Isolated mucosal cells were prepared from biopsies of normal mucosa and examined by antibodies against the same markers by immunofluorescence. RESULTS Normal gastrointestinal NE cells did not express E-cadherin as assessed by IHC or immunocytochemistry. No expression of E-cadherin was found on tumor cells from gastric carcinoids or cancer of diffuse type examined by IHC. CONCLUSION Our findings, which are in contrast to some previous studies, may explain why there is a discrepancy between lack of atypia and malignant biological behavior of such tumors. Since they normally lack the adhesion molecule E-cadherin, reflected in their spread occurrence, only minor changes may result in malignant behavior.
Collapse
Affiliation(s)
- Helge L Waldum
- Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology , Trondheim , Norway
| | | | | | | | | | | |
Collapse
|
|
13
|
Significance of dysadherin and E-cadherin expression in differentiated-type gastric carcinoma with submucosal invasion. Hum Pathol 2011; 42:558-67. [PMID: 21239043 DOI: 10.1016/j.humpath.2010.08.016] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2010] [Revised: 08/06/2010] [Accepted: 08/20/2010] [Indexed: 11/24/2022]
Abstract
Dysadherin is a cancer-associated cell membrane glycoprotein that down-regulates E-cadherin and plays important roles in tumor progression and metastasis. Differentiated-type gastric carcinoma can be classified into 2 histologic subtypes according to the presence of poorly differentiated components: a mixed type (differentiated carcinoma with poorly differentiated components) and a pure type (purely differentiated-type adenocarcinoma). We studied the clinicopathologic features of 318 cases of differentiated-type gastric carcinoma with submucosal invasion and evaluated the immunohistochemical expression of dysadherin and E-cadherin. We also evaluated 46 cases of metastatic lymph nodes. Tumors with combined dysadherin-positive (≥50%) expression and E-cadherin-negative (<50%) expression had significantly higher proportions of the moderately differentiated type, deeper submucosal invasion, positivity of lymphatic permeation, and positivity of lymph node metastasis than tumors with other combinations of dysadherin and E-cadherin expression (P = .0009, P = .0015, P = .0273, and P = .0187, respectively). Moreover, the frequency of dysadherin-positive (≥50%) expression was higher in the mixed type (60.3%) than in the pure type (12.4%) (P < .0001), whereas the frequency of E-cadherin-negative (<50%) expression was higher in the mixed type (84.5%) than in the pure type (50.5%) (P < .0001). The frequency of dysadherin expression in the metastatic lymph nodes (80.4%) was significantly higher than that in the primary tumors (45.7%) (P = .001). Dysadherin-positive (≥50%) expression and E-cadherin-negative (<50%) expression may be correlated with the mixed type. Combined dysadherin-positive (≥50%) expression and E-cadherin-negative (<50%) expression may be valuable information for predicting aggressive tumor behavior.
Collapse
|
|
14
|
Molecular interactions in cancer cell metastasis. Acta Histochem 2010; 112:3-25. [PMID: 19162308 DOI: 10.1016/j.acthis.2008.11.022] [Citation(s) in RCA: 202] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2008] [Revised: 11/13/2008] [Accepted: 11/13/2008] [Indexed: 02/08/2023]
Abstract
Metastasis, the process by which cancer cells leave the primary tumour, disseminate and form secondary tumours at anatomically distant sites, is a serious clinical problem as it is disseminated disease, which is often impossible to eradicate successfully, that causes the death of most cancer patients. Metastasis results from a complex molecular cascade comprising many steps, all of which are interconnected through a series of adhesive interactions and invasive processes as well as responses to chemotactic stimuli. In spite of its clinical significance, it remains incompletely understood. This review provides an overview of some of the molecular interactions that are critical to metastasis. It summarises the principle molecular players in the major steps of the metastatic cascade. These are: (1) tumour angiogenesis, (2) disaggregation of tumour cells from the primary tumour mass, mediated by cadherins and catenins, (3) invasion of, and migration through, the basement membrane (BM) and extracellular matrix (ECM) surrounding the tumour epithelium, and subsequent invasion of the BM of the endothelium of local blood vessels. This is mediated through integrins and proteases, including urokinase form of plasminogen activator (uPA), matrix metalloproteinases (MMPs) and cathepsins, (4) intravasation of the tumour cells into the blood vessels prior to hematogeneous dissemination to distant sites, (5) adhesion of the circulating tumour cells to the endothelial cell lining at the capillary bed of the target organ site. This occurs through adhesive interactions between cancer cells and endothelial cells involving selectins, integrins and members of the immunoglobulin superfamily (IgSF), (6) invasion of the tumour cells through the endothelial cell layer and surrounding BM (extravasation) and target organ tissue and (7) the development of secondary tumour foci at the target organ site.
Collapse
|
|
15
|
Yalta T, Atay L, Atalay F, Çaydere M, Gonultas M, Ustun H. E-Cadherin Expression in Endometrial Malignancies: Comparison between Endometrioid and Non-Endometrioid Carcinomas. J Int Med Res 2009; 37:163-8. [DOI: 10.1177/147323000903700119] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
This study examined the frequency of E-cadherin expression in endometrial biopsy or hysterectomy specimens from patients diagnosed with endometrial adenocarcinoma and in normal endometrial tissue specimens. E-cadherin expression was detected by immunohistochemistry using monoclonal antibody to E-cadherin. Specimens were classified as positive when ≥ 5% of the tumour cells showed staining for E-cadherin, irrespective of the pattern of staining. Twenty-three endometrioid carcinomas and nine non-endometrioid (four papillary serous and five clear cell) carcinomas were studied, along with 10 normal endometrial tissue specimens as controls. E-cadherin expression was significantly less frequent in non-endometrioid carcinomas compared with endometrioid carcinomas and controls. There was no statistically significant difference in the frequency of E-cadherin expression between endometrioid carcinomas and controls. In conclusion, this study demonstrated that uterine non-endometrioid (papillary serous and clear cell) carcinomas were less likely to express E-cadherin compared with endometrioid carcinomas and normal endometrial tissue. This may help to explain the more aggressive behaviour of non-endometrioid carcinomas.
Collapse
Affiliation(s)
- T Yalta
- Pathology Department, Sivas State Hospital, Sivas, Turkey
| | - L Atay
- Pathology Department, Ankara Training and Research Hospital, Ankara, Turkey
| | - F Atalay
- Pathology Department, Ankara Training and Research Hospital, Ankara, Turkey
| | - M Çaydere
- Pathology Department, Ankara Training and Research Hospital, Ankara, Turkey
| | - M Gonultas
- Pathology Department, Ankara Training and Research Hospital, Ankara, Turkey
| | - H Ustun
- Pathology Department, Ankara Training and Research Hospital, Ankara, Turkey
| |
Collapse
|
|
16
|
Yi Kim D, Kyoon Joo J, Kyu Park Y, Yeob Ryu S, Soo Kim H, Kyun Noh B, Hwa Lee K, Hyuk Lee J. E-cadherin expression in early gastric carcinoma and correlation with lymph node metastasis. J Surg Oncol 2007; 96:429-35. [PMID: 17786966 DOI: 10.1002/jso.20732] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVE Abnormal expression of E-cadherin plays an important role in the differentiation and progression of gastric carcinoma. However, the relationship between molecular changes in E-cadherin and metastasis in early gastric carcinoma (EGC) is poorly understood. MATERIALS AND METHODS Sixty cases of EGC with or without lymph node metastasis (30 node-positive cases and 30 node-negative cases) were investigated to evaluate hypermethylation status using bisulfate-MSP and immunohistochemistry using antibody against E-cadherin. RESULTS Twenty-seven (45.0%) of 60 primary EGCs exhibited methylation in the CpG island of E-cadherin. Abnormal expression of E-cadherin was significantly correlated with patient age, tumor size, Lauren classification, differentiation, and lymph node metastasis. Using multiple logistic regression analysis, two factors were independent, statistically significant parameters associated with lymph node metastasis: abnormal expression of E-cadherin (risk ratio, 2.62; 95% confidence interval, 0.917-7.457; P < 0.05) and lymphatic invasion (risk ratio, 8.11; 95% confidence interval, 1.612-40.766; P < 0.05). CONCLUSION Our results suggest that methylation of E-cadherin is a frequent, early event in gastric carcinoma progression, and is correlated significantly with downregulated E-cadherin expression. Inactivation of E-cadherin might be involved in metastasis in EGC and play an important role in microscopic differentiation.
Collapse
Affiliation(s)
- Dong Yi Kim
- Division of Gastroenterologic Surgery, Department of Surgery, Chonnam National University Medical School, Dongku, Gwangju, Korea
| | | | | | | | | | | | | | | |
Collapse
|
|
17
|
Vukobrat-Bijedić Z, Radović S, Husić-Selimović A, Gornjaković S. Tumor suppresser gene p53 expression in premalignant lesions and gastric carcinoma - prognostic value. Bosn J Basic Med Sci 2007; 7:7-10. [PMID: 17489760 PMCID: PMC5802291 DOI: 10.17305/bjbms.2007.3080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
The aim of the study was to verify the presence of mutated tumor suppresser gene p53 in intestinal mucosa with histologically confirmed premalignant lesions and gastric carcinoma, and assess its prognostic value. The paper presents prospective study that included 50 patients with gastric adeno-carcinoma of intestinal type that were treated at Gastroenterohepatology Clinic, and 50 patients with histologically confirmed chronic atrophic H. pylori positive gastritis. In the mucosa biopsy samples, we analyzed presence, frequency and severity of inflammatory-regenerative, metaplastic and dysplastic changes. We typed intestinal metaplasia immunohistochemically and confirmed the presence of p53 onco-protein in antigen positive gastric carcinoma cells, and evaluated its prognostic value. Our results suggest that H. pylori acts as an initiator of inflammatory processes in gastric mucosa, which are followed by emergence of precancerous lesions. p53 is expressed late in carcinogenesis (14%) and as such, may be considered as an indicator of transformation of premalignant into malignant lesion.
Collapse
Affiliation(s)
- Zora Vukobrat-Bijedić
- Gastroenterohepatology Clinic, University of Sarajevo Clinics Center, Bolnicka 25, 71000 Sarajevo, Bosnia and Herzegovina
| | | | | | | |
Collapse
|
|
18
|
Leung WK, Man EPS, Yu J, Go MYY, To KF, Yamaoka Y, Cheng VYY, Ng EKW, Sung JJY. Effects of Helicobacter pylori eradication on methylation status of E-cadherin gene in noncancerous stomach. Clin Cancer Res 2006; 12:3216-21. [PMID: 16707623 DOI: 10.1158/1078-0432.ccr-05-2442] [Citation(s) in RCA: 97] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
PURPOSE Promoter hypermethylation of E-cadherin plays an important role on gastric cancer development. Whereas E-cadherin methylation was frequently detected in the stomach of Helicobacter pylori-infected individuals, we tested whether eradication of H. pylori alters the methylation status of the noncancerous gastric epithelium. EXPERIMENTAL DESIGN Endoscopic biopsies were taken from the antrum and corpus of H. pylori-infected subjects without gastric cancer. Presence of methylated E-cadherin sequences in the gastric specimens was detected by methylation-specific PCR. Bisulfite DNA sequencing was done to determine the topographical distribution and changes in methylation profiles with H. pylori eradication. RESULTS Among the 28 H. pylori-infected subjects (median age, 44.5 years), 15 (53.6%) had E-cadherin methylation detected in stomach at baseline. Discordant methylation patterns between the antrum and corpus were noted in six patients. One year after successful H. pylori eradication, there was a significant reduction in the methylation density of the promoter region and exon 1 of the E-cadherin gene as detected by bisulfite DNA sequencing (P < 0.001). CONCLUSION Promoter methylation in E-cadherin was frequently detected in the stomach of H. pylori-infected individuals. Eradication of H. pylori might possibly reduce the methylation density in E-cadherin gene and the chance of subsequent neoplastic transformation.
Collapse
Affiliation(s)
- Wai K Leung
- Institute of Digestive Disease, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong.
| | | | | | | | | | | | | | | | | |
Collapse
|
|
19
|
Stock M, Otto F. Gene deregulation in gastric cancer. Gene 2005; 360:1-19. [PMID: 16154715 DOI: 10.1016/j.gene.2005.06.026] [Citation(s) in RCA: 94] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2005] [Revised: 05/26/2005] [Accepted: 06/13/2005] [Indexed: 12/21/2022]
Abstract
Despite its decreasing frequency in the Western world during recent decades, gastric cancer is still one of the leading causes of cancer-related deaths worldwide. Due to the oligosymptomatic course of early gastric cancer, most cases are diagnosed in the advanced stages of the disease. The curative potential of current standard treatment continues to be unsatisfactory, despite multimodal approaches involving surgery, chemotherapy and radiotherapy. Novel therapeutics including small molecules and monoclonal antibodies are being developed and have been partially introduced into clinical use in connection with neoplastic diseases such as chronic myeloid leukemia, non-Hodgkin's lymphoma and colorectal cancer. Thorough understanding of the changes in gene expression occurring during gastric carcinogenesis may help to develop targeted therapies and improve the treatment of this disease. Novel molecular biology techniques have generated a wealth of data on up- and down-regulation, activation and inhibition of specific pathways in gastric cancer. Here, we provide an overview of the different aspects of aberrant gene expression patterns in gastric cancer.
Collapse
Affiliation(s)
- Michael Stock
- Department of Hematology and Oncology, University Hospital Freiburg, Hugstetter Strasse 55, D-79106 Freiburg, Germany
| | | |
Collapse
|
|
20
|
Zhou YN, Xu CP, Chen Y, Han B, Yang SM, Fang DC. α-catenin expression is decreased in patients with gastric carcinoma. World J Gastroenterol 2005; 11:3468-72. [PMID: 15948257 PMCID: PMC4316006 DOI: 10.3748/wjg.v11.i22.3468] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To assess the expression of α-catenin in gastric carcinoma and to determine the role of α-catenin expression in gastric carcinogenesis.
METHODS: α-catenin expression was assessed by semi-quantitative reverse transcriptase-polymerase chain reaction and immunohistochemical staining in 49 gastric carcinomas, 26 adjacent non-cancerous mucosae, and gastric biopsy specimens from 11 healthy controls.
RESULTS: mRNA levels of α-catenin were reduced or absent in 34 of 49 (69%) gastric carcinoma tissues and in 5 of 26 (19%) tumor-free gastric mucosae of carcinoma patients, respectively. Of the carcinoma samples with altered α-catenin mRNA levels, α-catenin expression was negative in 20 and decreased in 14 cases. Up to 69% of tumors were stained abnormally for α-catenin. Of the 34 cases whose mRNA expression of α-catenin was reduced, 32 (94%) showed abnormal immunostaining patterns, while only 2 showed a normal α-catenin expression. The frequency of reduced expression of α-catenin mRNA was 14% in well-differentiated carcinomas, higher than that in poorly differentiated carcinomas (86%). A significant correlation was not shown between α-catenin expression and both depth of invasion and lymph node metastasis. Moreover, there was no statistical difference between loss or down-regulation of α-catenin mRNA and Helicobacter pylori (H pylori) infection.
CONCLUSION: Downregulation of α-catenin expression is common in gastric carcinoma, and α-catenin expression may be used as a differentiation marker. Downregulation of α-catenin expression may be an early event in tumorigenesis. Reduced α-catenin expression is not correlated with H pylori infection.
Collapse
Affiliation(s)
- Yong-Ning Zhou
- Department of Gastroenterology, First Hospital, Lanzhou University, Lanzhou 730000, Gansu Province, China.
| | | | | | | | | | | |
Collapse
|
|
21
|
Huang MF, Zhu YQ, Chen ZF, Xiao J, Huang X, Xiong YY, Yang GF. Syndecan-1 and E-cadherin expression in differentiated type of early gastric cancer. World J Gastroenterol 2005; 11:2975-80. [PMID: 15902740 PMCID: PMC4305671 DOI: 10.3748/wjg.v11.i19.2975] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To elucidate the role and alterations of syndecan-1 and E-cadherin expression in different cellular phenotypes of differentiated-type gastric cancers (DGCs).
METHODS: A total of 120 DGCs at an early stage, and their adjacent mucosa, were studied both by immunohis-tochemistry. Syndecan-1 and E-cadherin were assessed by immunohistochemical staining with anti-syndecan-1 and anti-E-cadherin antibodies, respectively. Based on immunohistochemistry, DGCs and their surrounding mucosa were divided into four types: gastric type (G-type), ordinary type (O-type), complete-intestinal type (CI-type), and null type (N-type).
RESULTS: Syndecan-1 expression was significantly lower in G-type cancers (29.4%) than in O-type (79.6%) and CI-type cancers (90%) (P<0.05, respectively), but E-cadherin did not show this result. In addition, syndecan-1 expression was significantly reduced in DGCs comprised partly of poorly differentiated adenocarcinoma or signet-ring cell carcinoma, compared to DGCs demonstrating papillary and/or tubular adenocarcinoma (P<0.05). G-type intestinal metaplasia (IM) surrounding the tumors was observed in 23.8% of G-type, 4.9% of O-type, and 6.7% of CI-type cancers (P<0.05; G-type vs O-type). Reduction of syndecan-1 expression was significant in G-type IM (25%) compared to non-G-type IM (75%; P<0.05).
CONCLUSION: Loss of syndecan-1 plays a role in the growth of G-type cancers of DGCs at an early stage, and the reduction of syndecan-1 expression in IM surrounding the tumors may influence the growth of G-type cancer.
Collapse
Affiliation(s)
- Mei-Fang Huang
- Department of Digestive Disease, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | | | | | | | | | | | | |
Collapse
|
|
22
|
Cheng XX, Wang ZC, Chen XY, Sun Y, Kong QY, Liu J, Li H. Correlation of Wnt-2 expression and beta-catenin intracellular accumulation in Chinese gastric cancers: relevance with tumour dissemination. Cancer Lett 2004; 223:339-47. [PMID: 15896469 DOI: 10.1016/j.canlet.2004.11.013] [Citation(s) in RCA: 68] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2004] [Revised: 10/30/2004] [Accepted: 11/02/2004] [Indexed: 12/16/2022]
Abstract
Wnt/beta-catenin signalling pathway is integrally associated with human tumour development and progression. Aberrant beta-catenin intracellular distribution has been found in gastric cancer, but the pattern of Wnt expression in stepwise gastrocarcinogenesis and its potential influence in beta-catenin distribution are still lesser known. By the methods of frozen tissue array-based immunohistochemistry, Western blot analysis and RT-PCR, a paralleled study was conducted to check Wnt2 expression and beta-catenin intracellular distribution in two major subtypes of gastric cancers (intestinal gastric cancer, i-GC and diffuse gastric cancer, d-GC) and their premalignant (intestinal metaplasia, IM and chronic gastritis, CG) and noncancerous counterparts. According to the results obtained and the clinical data collected, correlation of Wnt2 expression with beta-catenin translocalisation and their links with tumour dissemination were elucidated. The results demonstrated (1) that Wnt2 expression and cytoplasmic/nuclear beta-catenin accumulations appeared in most gastric cancers irrespective to their morphological phenotypes, (2) that over-expressed Wnt and nuclear translocalisation of beta-catenin were found in 68 and 58% of i-GCs and in 47 and 47% of d-GCs in a closely related pattern (P<0.01) and (3) that co-existence of Wnt2 up-regulation/beta-catenin nuclear translocalisation were positively associated with lymph node metastasis (P<0.05) as well as T-stage. These data indicate that Wnt/beta-catenin signalling pathway is activated in most of gastric cancers, which may play pivotal roles either in gastric cancer formation or in tumour invasion and dissemination.
Collapse
Affiliation(s)
- Xiao-Xin Cheng
- Cancer Institute, College of Basic Medical Sciences, Dalian Medical University, Dalian 116027, People's Republic of China
| | | | | | | | | | | | | |
Collapse
|
|
23
|
Abstract
This paper provides a bird’s-eye view both in preclinical and clinical aspects of E-cadherin germline gene (CDH1) in gastric cancer patients and their families. E-cadherin, a product of CDH1 gene, belonging to the functionally related trans-membrane glycoprotein family, is responsible for the Ca2+-dependent cell-cell adhesion mechanism and contributes to dissociation followed by acquisition of cell motility, which usually occurs in the first step of cancer invasion and metastasis. CDH1 gene germline mutation is common in many types of carcinoma, and occurs very frequent in hereditary gastric carcinoma (HGC) patients and their families. Recently, more and more researches support that E-cadherin plays an important role in the differentiation, growth and invasion of HGC. So it is of great value to clarify its mechanisms both for understanding HGC pathogenesis and for clinical therapy, especially in China, where there are a high risk population of gastric cancer and a high HGC incidence rate. In this paper, recent researches on CDH1 gene mutation, especially its role in tumor genesis and progress of HGC, are reviewed, and advances in evaluation of its mutation status for HGC diagnosis, therapy and prognosis, are also discussed briefly.
Collapse
Affiliation(s)
- Hai-Dan Wang
- Center of Clincal Oncology and International Collaborative Group on Hereditary Gastric Carcinoma, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, Shannxi Province, China
| | | | | |
Collapse
|
|
24
|
Zhang HK, Zhang QM, Zhao TH, Li YY, Yi YF. Expression of mucins and E-cadherin in gastric carcinoma and their clinical significance. World J Gastroenterol 2004; 10:3044-7. [PMID: 15378790 PMCID: PMC4576269 DOI: 10.3748/wjg.v10.i20.3044] [Citation(s) in RCA: 38] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM: To investigate the expression of three types of mucin (MUC1, MUC2, MUC5AC) and E-cadherin in human gastric carcinomas and their clinical significance.
METHODS: Ninety-four gastric cancer specimens were classified according to WHO criteria and detected by immun-ohistochemical assay of expression of mucins and E-cadherin.
RESULTS: The positive expression rates of MUC1, MUC2, MUC5AC and E-cadherin were 82% (77/94), 84% (79/94), 40% (38/94) and 56% (53/94) respectively. MUC1 expression was significantly correlated with the types of cancer (the positive rates of MUC1 in well and moderately differentiated tubular adenocarcinoma, poorly differentiated adenocarcinoma, signet-ring cell carcinoma and mucinous carcinoma were 91%, 87%, 71%, 71%, respectively, P < 0.05), age of patients (the positive rates of it among the people who are younger than 40 years, between 40-60 years and over 60 year were 74%, 81%, 89%, P < 0.05), lymph nodes involvement (the positive rates in the non-interfered group and the interfered group were 78%, 85%, P < 0.05) and tumor size (the positive rates in the tumors with the size less than 3 cm, 3-6 cm and larger than 6 cm were 69%, 92%, 69%, P < 0.05); MUC2 expression was significantly associated with types of cancers and had the strongest expression in mucinous carcinomas (the positive rates of MUC2 in well and moderately differentiated tubular adenocarcinoma, poorly differentiated adenocarcinoma, signet-ring cell carcinoma and mucinous carcinoma were 94%, 70%, 81%, 100%, P < 0.05), but it had no obvious relation to age, gender, tumor location, lymph nodes involvement, depth of invasion and metastasis to extra-gastric organs (P > 0.05); MUC5AC expression was not related to any of the characteristics investigated except that it had relation to gender, whereas MUC5AC showed the tendency to higher expression in less invasive lesions and lower expression in advanced stage cancers (P > 0.05); No significant difference was found for E-cadherin expression. There were strong positive relationships between the expression of MUC1 and E-cadherin, MUC2 and E-cadherin, MUC1 and MUC2 (R = 0.33, R = 0.22, R = 0.32, respectively, P < 0.05). According to the COX proportional hazards model, older patients, involvement of lymph nodes, different types of gastric cancer and MUC2 expression were significantly associated with poorer outcome of gastric carcinoma patients (β = 0.08, β = 3.94, β = 1.33, β = 0.75, respectively, P < 0.05).
CONCLUSION: MUC1 and MUC2 are good markers of different types of gastric cancer. MUC2 is especially a good marker of mucinous carcinoma. MUC1, MUC2 may interfere with the function of E-cadherin in gastric carcinomas, and have synergic effect on progression of gastric cancers.
Collapse
Affiliation(s)
- Hong-Kai Zhang
- Department of Pathology, Fuxing Hospital, Capital University of Medical Sciences, Beijing 100038, China
| | | | | | | | | |
Collapse
|
|
25
|
Song SY, Kim S, Kim DS, Son HJ, Rhee JC, Kim YI. Abnormal expression of E-cadherin in early gastric carcinoma: its relationship with macroscopic growth patterns and catenin alpha and beta. J Clin Gastroenterol 2004; 38:252-9. [PMID: 15128072 DOI: 10.1097/00004836-200403000-00011] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
BACKGROUND Abnormal expression of E-cadherin plays an important role in the differentiation and progression of gastric carcinoma. There are a few identifiable clinical, histopathologic, and molecular changes that are related with the macroscopic growth patterns of gastric carcinoma. The aim of this study is to elucidate the relation between the macroscopic growth patterns of gastric carcinoma and the abnormal expression of E-cadherin, alpha- and beta-catenins. STUDY A total of 97 cases of early gastric carcinoma were examined by immunohistochemistry using monoclonal antibodies against E-cadherin, alpha- and beta-catenins. Macroscopically, 52 cases were elevated types and 45 cases were depressed types. RESULTS Early gastric carcinomas with depressed growth showed diffuse histologic type, younger patients' age and smaller size more frequently than tumors with elevated growth. Abnormal expression rates of E-cadherin, alpha- and beta-catenins were 35.1, 36.1, and 46.4%, respectively. Abnormal expression of E-cadherin, alpha- and beta-catenins was significantly associated with depressed tumor growth and diffuse histologic type. By multiple logistic regression analysis. E-cadherin, age, Lauren classification, World Health Organization grade and size were identified as risk factors of macroscopic growth pattern of early gastric carcinomas. Positive associations between E-cadherin and beta-catenin and between alpha- and beta-catenins were found by log linear model analysis. CONCLUSION We suggest that E-cadherin plays an important role in the macroscopic growth as well as microscopic differentiation of early gastric carcinomas.
Collapse
Affiliation(s)
- Sang Yong Song
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | | | | | | | | | | |
Collapse
|
|
26
|
Chen HC, Chu RY, Hsu PN, Hsu PI, Lu JY, Lai KH, Tseng HH, Chou NH, Huang MS, Tseng CJ, Hsiao M. Loss of E-cadherin expression correlates with poor differentiation and invasion into adjacent organs in gastric adenocarcinomas. Cancer Lett 2003; 201:97-106. [PMID: 14580691 DOI: 10.1016/j.canlet.2003.07.007] [Citation(s) in RCA: 64] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Perturbation in E-cadherin expression leads to loss of cellular adhesion with possible consequence of cellular transformation and tumor progression. The aims of this study were to determine E-cadherin expression in each subtype of gastric cancer classified by different classification systems, and to investigate the role of E-cadherin in cell differentiation, cancer invasion and metastasis. Expression of E-cadherin was analyzed in 84 patients with gastric adenocarcinoma by immunohistochemistry and correlated with clinicopahotlogical parameters. Our results showed loss of E-cadherin expression in 0% (0/3), 20.0% (9/45), 48% (15/31), 100% (3/3) and 100% (2/2) of papillary, tubular, poorly differentiated, signet-ring cell, and mucinous adenocarcinoma by Japanese histological classification. The reduction of E-cadherin expression was inversely correlated with the grade of differentiation. According to the histological classification of Lauren and Ming, the frequency of lost E-cadherin expression was higher in diffuse type (65%) and infiltrative type (64%) gastric cancer than in intestinal type (20%, P<0.001) and expanding type cancer (22%, P<0.001), respectively. The loss of E-cadherin expression was significantly associated with tumor invasion (P<0.05). Furthermore, there was a borderline association between the loss of E-cadherin expression and poor survival (P=0.109). These data demonstrated a striking correlation between E-cadherin expression and the differentiation of gastric carcinoma. The loss of E-cadherin expression may contribute to gastric cancer invasion to adjacent organs.
Collapse
Affiliation(s)
- Hui-Chun Chen
- Department of Radiation Oncology, Chang Gung Memorial Hospital-Kaohsiung, Taiwan ROC
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
27
|
Gulmann C, Grace A, Leader M, Butler D, Patchett S, Kay E. Adenomatous polyposis coli gene, beta-catenin, and E-cadherin expression in proximal and distal gastric cancers and precursor lesions: an immunohistochemical study using tissue microarrays. Appl Immunohistochem Mol Morphol 2003; 11:230-7. [PMID: 12966349 DOI: 10.1097/00129039-200309000-00005] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
The aims of this study were (1) to compare protein expression of adenomatous polyposis coli (APC) gene, beta-catenin, and E-cadherin between proximal and distal gastric adenocarcinomas and (2) to investigate their use as markers of cancer risk in intestinal metaplasia (IM). The epidemiology of proximal (cardia and gastroesophageal junction) and distal (antrum and corpus) gastric carcinomas is strikingly different despite similar morphologies. Carcinoma of the distal stomach is decreasing in incidence, whereas proximal carcinomas are increasing in incidence more than any other cancer in the Western world. This phenomenon has so far not been satisfactorily explained. IM is a well-established precursor for adenocarcinoma in the distal stomach but less so in the proximal stomach. However, its specificity as a predictor of gastric carcinoma is very low. Abnormalities of APC, beta-catenin, and E-cadherin are implicated in carcinogenesis of the stomach and may show aberrant expression at early stages of the neoplastic process. This study evaluated their immunoprofiles in 3 groups: biopsies showing normal mucosa (n = 108), biopsies showing IM (n = 99), and gastric cancer resections (n = 117). In the last group, carcinoma and noninvolved mucosa were studied. All groups included material from both proximal and distal locations. The results of this study showed that there were no differences between proximal and distal locations with regard to APC, beta-catenin, or E-cadherin expression. In both locations, high normal expression rates for all 3 molecules were present in biopsies showing normal gastric mucosa or IM and noninvolved mucosa from gastric cancer resections. In carcinomas, there was a significant decrease in both APC and E-cadherin expression, whereas beta-catenin showed abnormal cytoplasmic and nuclear staining. Diffuse-type cancers showed significantly lower E-cadherin expression than intestinal types. Noninvolved mucosa from cancer resections showed normal APC, beta-catenin, and E-cadherin expression regardless of adjacent tumor type and whether the mucosa was morphologically normal or showed IM. In conclusion, proximal and distal gastric carcinomas show no differences in expression of APC, beta-catenin, or E-cadherin; thus, the observed abnormalities do not seem to contribute to the observed epidemiologic differences between these tumors. Because loss of APC, decreased E-cadherin, or abnormal beta-catenin expression did not occur in IM, even when associated with carcinoma these immunostains are unlikely to be of value in the assessment of malignant potential in IM.
Collapse
Affiliation(s)
- Christian Gulmann
- Department of Pathology, Beaumont Hospital and Royal College of Surgeons in Ireland, Dublin, Ireland.
| | | | | | | | | | | |
Collapse
|
|
28
|
Chan AOO, Wong BCY, Lan HY, Loke SL, Chan WK, Hui WM, Yuen YH, Ng I, Hou L, Wong WM, Yuen MF, Luk JMC, Lam SK. Deregulation of E-cadherin-catenin complex in precancerous lesions of gastric adenocarcinoma. J Gastroenterol Hepatol 2003; 18:534-9. [PMID: 12702045 DOI: 10.1046/j.1440-1746.2003.02998.x] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND AIM Decrease in expression of the E-cadherin-catenin complex is an important element in gastric carcinogenesis. However, the expression of the complex in gastric precancerous lesions has not been well studied. The present study aimed to examine the serial change in expression of E-cadherin-catenin complex in the precancerous lesions of gastric cancer patients. METHODS Gastrectomy specimens of 40 patients with gastric cancer were retrieved. Areas with chronic gastritis, atrophic gastritis, intestinal metaplasia and adenocarcinoma were identified and immunostained for alpha-catenin, beta-catenin and E-cadherin. The results were scored semiquantitatively by two independent pathologists using a validated scoring system. RESULTS A significant decrease in score was observed in 5% (1/22) of alpha-catenin, 0% (0/22) of beta-catenin and 9% (2/22) of E-cadherin in chronic atrophic gastritis patients, and in 28% (5/18) of alpha-catenin, 67% (10/15) of beta-catenin and 57% (8/14) of E-cadherin in intestinal metaplasia patients. The scoring of alpha-catenin, beta-catenin and E-cadherin correlated with each other. Forty-three percent of patients had concordant changes of scores along the gastritis-adenocarcinoma sequence. There was no association between Helicobacter pylori status and E-cadherin-catenin complex expression. CONCLUSION Deregulation of the E-cadherin-catenin complex was observed in the majority of precancerous lesions in patients with gastric adenocarcinoma, which has potential diagnostic and therapeutic implications.
Collapse
Affiliation(s)
- Annie On-On Chan
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong
| | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
29
|
Zhou YN, Xu CP, Han B, Li M, Qiao L, Fang DC, Yang JM. Expression of E-cadherin and β-catenin in gastric carcinoma and its correlation with the clinicopathological features and patient survival. World J Gastroenterol 2002; 8:987-93. [PMID: 12439911 PMCID: PMC4656404 DOI: 10.3748/wjg.v8.i6.987] [Citation(s) in RCA: 80] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: The E-cadherin-catenin complex is important for cell-cell adhesion of epithelial cells. Impairment of one or more components of this complex is associated with poor differentiation and increased invasiveness of carcinomas. We evaluated the expression pattern of E-cadherin and β-catenin in gastric carcinoma and dysplasia and analyzed their relationship with tumor clinicopathological features and patient survival.
METHODS: Immunohistochemical staining of E-cadherin and β-catenin was performed from paraffin specimens of 163 gastric carcinomas, 44 gastric mucosal dysplasia, and 25 intestinal metaplasia, 28 atrophic gastritis and 12 healthy controls.
RESULTS: Normal membrane staining was observed in intestinal metaplasia, atrophic gastritis and control biopsy specimens for E-cadherin and β-catenin. 36% and 16% of gastric dysplasia were stained abnormally for E-cadherin and β-catenin respectively. Abnormal expression of E-cadherin and β-catenin was demonstrated in 46% and 44% of gastric carcinoma respectively. Abnormal expression of E-cadherin and β- catenin occurred more significantly in Borrmann III/IV than in Borrmann I/II type (P < 0.005, respectively). A significantly higher proportion of signet-ring, mucinous and tubular adenocarcinomas were abnormally expressed for E-cadherin and β-catenin as compared with papillary adenocarcinomas (χ2 = 8.47, P < 0.005, and χ2 = 7.05, P < 0.01, respectively). Morever, abnormal E-cadherin and β-catenin staining occurred more frequently in diffuse than in intestinal type of tumor (χ2 = 18.18 and 17.79, P < 0.005, respectively). There was a significant correlation between abnormal β-catenin expression and positive lymph node metastasis. A survival advantage was noted in tumors retaining normal membranous expression of β-catenin, independent of type, grade, or stage of the disease (P < 0.0005).
CONCLUSION: Abnormal expression of the E-cadherin-catenin complex occurs frequently in gatric carcinoma, closely related to its histogenesis. Abnormal expression of the E-cadherin- catenin complex in gastric dysplasia may be an early event in the tumorigenesis. The close correlation with poor survival suggests that abnormal β-catenin may be a useful prognostic marker.
Collapse
Affiliation(s)
- Yong-Ning Zhou
- Department of Gastroenterology, Southwest Hospital, the Third Millitary Medical University, Chongqing, 400038, China.
| | | | | | | | | | | | | |
Collapse
|
|
30
|
Abstract
Decreased E-cadherin expression permits dissociation and widespread dissemination of gastric adenocarcinoma cells. We studied the relationship between paranuclear E-cadherin distribution and the histopathologic characteristics of gastric adenocarcinomas. E-cadherin immunostains of 173 gastric adenocarcinoma sections revealed paranuclear; punctate to vesicular staining in 18% (16/87) of the intestinal-type adenocarcinomas, 30% (17/56) of the diffuse-type adenocarcinomas, and 30% (9/30) of the mired adenocarcinomas. These data suggest that in some gastric adenocarcinomas, there is a defect in transport of E-cadherin to the cell surface, which may prevent intercellular adhesion and encourage dissemination. Of 34 cancers with paranuclear E-cadherin staining, 20 (59%) had paranuclear staining within the nonneoplastic epithelium, but only 22.0% of 100 carcinomas with absent or membranous E-cadherin staining were accompanied by morphologically benign epithelium with paranuclear E-cadherin. In surface epithelium, paranuclear E-cadherin staining colocalized with Griffonia simplicifolia lectin II in the Golgi apparatus. The presence of paranuclear E-cadherin in cancer-associated benign epithelium suggests that the alteration in the E-cadherin molecule responsible for the paranuclear distribution may be an early change in gastric adenocarcinoma progression.
Collapse
Affiliation(s)
- Philip M Carpenter
- Department of Pathology, University of California, Irvine Medical Center, Orange 92868, USA
| | | | | |
Collapse
|
|
31
|
Kozuki T, Yao T, Nakamura S, Matsumoto T, Tsuneyoshi M. Differences in p53 and cadherin-catenin complex expression between histological subtypes in diffusely infiltrating gastric carcinoma. Histopathology 2002; 41:56-64. [PMID: 12121238 DOI: 10.1046/j.1365-2559.2002.01407.x] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
AIMS The aim of this study was to elucidate possible clinicopathological differences between diffusely infiltrating gastric carcinoma of 'pure type' (poorly differentiated carcinoma without any glandular component) and 'mixed type' (coexistence of poorly differentiated carcinoma and intramucosal glandular component). METHODS AND RESULTS The clinicopathological features and immunohistochemical expression of p53 and intercellular adhesion molecules (E-cadherin and alpha-, beta- and gamma-catenins) were compared between the patients with pure (n=59) and mixed (n=56) types of diffusely infiltrating gastric carcinoma. Intestinal metaplasia (P < 0.01), prominent lymphatic permeation (P < 0.001) and lymph node metastasis (P < 0.05) were more frequently observed in mixed type than in pure type, while survival probability did not differ between the two groups. The frequency of p53 over-expression was higher in mixed type (56%) than in pure-type (19%) (P < 0.001). In mixed type, p53 expression was not different between glandular and poorly differentiated components. By contrast, the expression of adhesion molecules was more frequently preserved in glandular components than in poorly differentiated components. CONCLUSIONS These two subtypes seem to be different in nature and biological behaviour. The preservation of adhesion molecules in mixed type may be associated with higher incidence of lymphatic permeation and lymph node metastasis.
Collapse
Affiliation(s)
- T Kozuki
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | | | | | | | | |
Collapse
|
|
32
|
Abstract
E-cadherin and its associated cytoplasmic proteins including alpha-, beta-, and gamma-catenin play a pivotal role in the maintenance of normal tissue architecture and the suppression of cancer invasion. The purpose of this study was to evaluate the expression of E-cadherin and alpha-, beta-, and gamma-catenin in a larger sample of early gastric cancer, and to examine the relation between these expressions and various clinicopathologic variables. The expression of E-cadherin and alpha-, beta-, and gamma-catenin was investigated using immunohistochemical technique with formalin-fixed, paraffin-embedded tissue specimens obtained from 108 patients who underwent surgery for early gastric cancer. In the gastric mucosa of noncancerous areas, epithelial cells showed equally strong membranous expression of E-cadherin and alpha-, beta-, and gamma-catenin proteins at the cell-cell boundaries. Reduced expression of E-cadherin and alpha-, beta-, and gamma-catenin was demonstrated in 43.5%, 39.8%, 42.6%, and 50% of cancer tissues, respectively. Whereas 34 tumors (31.5%) displayed preserved expression of all four E-cadherin-catenin complex components, 21 tumors (19.4%) displayed reduced expression of all components of this complex. Reduced expression of E-cadherin and alpha- and gamma-catenin occurred more frequently in diffuse than in intestinal types of cancer, and decreased expression of E-cadherin and alpha-, beta-, and gamma-catenin correlated with poor differentiation. The expression of E-cadherin and beta- and gamma-catenin did not correlate with the patient's age, gender, tumor size, location, macroscopic type, depth of invasion, or lymph node metastasis. Only reduced expression of alpha-catenin correlated with lymph node metastasis. Reduced expression of all four E-cadherin-catenin complex components correlated with poorly differentiated and diffuse-type cancers, but not with the patient's age, gender, tumor size, location, macroscopic type, depth of invasion, or lymph node metastasis. These results suggest that dysfunction of the E-cadherin-catenin complex occurs in an early stage of carcinogenesis, playing a crucial role in disruption of tissue architecture and loss of differentiation in early gastric cancer.
Collapse
Affiliation(s)
- Young-Eun Joo
- Department of Internal Medicine, Chonnam National University Medical School, Kwangju, Korea.
| | | | | | | | | | | |
Collapse
|
|
33
|
Tanaka M, Kitajima Y, Edakuni G, Sato S, Miyazaki K. Abnormal expression of E-cadherin and beta-catenin may be a molecular marker of submucosal invasion and lymph node metastasis in early gastric cancer. Br J Surg 2002. [PMID: 11856141 DOI: 10.1046/j.1365-2168.2002.01985.x] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
BACKGROUND Impaired expression of E-cadherin and alpha- and beta-catenin is frequently observed in several human cancers. The aim of this study was to examine immunohistochemical expression of these adhesion molecules, focusing on early gastric carcinomas, and to investigate differences between differentiated and undifferentiated gastric cancer at the early phase of carcinogenesis. METHODS Immunohistochemical staining of E-cadherin and alpha- and beta-catenin was performed using specimens from 143 patients with early gastric cancer. RESULTS Abnormal E-cadherin and beta-catenin staining correlated with depth of tumour invasion in differentiated-type tumours. In contrast, abnormal staining was frequently found even in intramucosal carcinoma of undifferentiated-type tumours, suggesting an apparent difference in the onset of E-cadherin-catenin complex abnormality between the two cancer types. Absent staining of beta-catenin was associated with lymph node metastasis. Multivariate analysis revealed abnormal E-cadherin expression as an independent factor that correlated with submucosal invasion in early gastric cancer. CONCLUSION Abnormal E-cadherin expression is a possible marker of submucosal invasion in differentiated-type early gastric cancer and absent beta-catenin staining could be used as a predictor of lymph node metastasis in both types.
Collapse
Affiliation(s)
- M Tanaka
- Department of Surgery, Saga Medical School, 5-1-1 Nabeshima, Saga, 849-8501, Japan.
| | | | | | | | | |
Collapse
|
|
34
|
Silberg DG, Sullivan J, Kang E, Swain GP, Moffett J, Sund NJ, Sackett SD, Kaestner KH. Cdx2 ectopic expression induces gastric intestinal metaplasia in transgenic mice. Gastroenterology 2002; 122:689-96. [PMID: 11875002 DOI: 10.1053/gast.2002.31902] [Citation(s) in RCA: 350] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS Intestinal-type gastric cancer is often preceded by intestinal metaplasia in humans. The genetic events responsible for the transdifferentiation that occurs in intestinal metaplasia are not well understood. Cdx2, a transcription factor whose expression is normally limited to the intestine, has been detected in gastric intestinal metaplasia. Cdx2 induces differentiation of intestinal epithelial cells in vitro; therefore, we sought to establish whether a causal relationship exists between Cdx2 activation and intestinal metaplasia. METHODS Cdx2 expression was directed to the gastric mucosa in transgenic mice using cis-regulatory elements of Foxa3 (Hnf3gamma). Transgenic mice were analyzed for histologic and gene expression changes. RESULTS Histologic examination of the gastric mucosa of the Foxa3/Cdx2 mice revealed the presence of alcian blue-positive intestinal-type goblet cells, a hallmark of intestinal metaplasia. In addition, Cdx2 induced the expression of intestine-specific genes. CONCLUSIONS Gastric expression of Cdx2 alone was sufficient to induce intestinal metaplasia in mice. These mice represent a powerful tool to investigate the molecular mechanisms that promote intestinal metaplasia. Moreover, as gastric cancer in humans is often preceded by intestinal metaplasia, the phenotype described here strongly suggests involvement of Cdx2 in the initiation of the process leading to intestinal neoplasia of the gastric mucosa.
Collapse
Affiliation(s)
- Debra G Silberg
- Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
| | | | | | | | | | | | | | | |
Collapse
|
|
35
|
Moriyama N, Ishihara S, Hirose M, Watanabe S, Sato N, Kinoshita Y. E-cadherin is essential for gastric epithelial restitution in vitro: a study using the normal rat gastric mucosal cell line RGM1. THE JOURNAL OF LABORATORY AND CLINICAL MEDICINE 2001; 138:236-42. [PMID: 11574817 DOI: 10.1067/mlc.2001.118177] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The proliferation and migration of epithelial cells appear to have important roles in intercellular adhesion and the regeneration of gastric mucosal lesions. However, the role of E-cadherin, an important intercellular adhesion molecule, in restitution after gastric mucosal damage is unknown. This study was designed to investigate the possible role of E-cadherin in the regeneration of gastric mucosal lesions. Artificial small wounds were made in an RGM1 confluent monolayer sheet, and the healing process was monitored with or without the presence of different concentrations of anti-E-cadherin antibodies. E-cadherin mRNA and protein expression were determined by Northern blot analysis and immunostaining, respectively. Epithelial restitution in anti-E-cadherin antibody-treated monolayers was inhibited as compared with that in the controls without antibody. E-cadherin mRNA and protein expression were up-regulated transiently during the healing process. E-cadherin plays an important role during wound healing of gastric epithelial lesions and is crucial for sheet migration.
Collapse
Affiliation(s)
- N Moriyama
- Second Department of Internal Medicine, Shimane Medical University, Shimane, Japan
| | | | | | | | | | | |
Collapse
|
|
36
|
Devereux TR, Stockton P, Sun K, Sills RC, Clayton N, Portier M, Flake G. Loss of E-cadherin expression in gastric intestinal metaplasia and later stage p53 altered expression in gastric carcinogenesis. EXPERIMENTAL AND TOXICOLOGIC PATHOLOGY : OFFICIAL JOURNAL OF THE GESELLSCHAFT FUR TOXIKOLOGISCHE PATHOLOGIE 2001; 53:237-46. [PMID: 11665847 DOI: 10.1078/0940-2993-00190] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Gastric cancers are commonly subdivided into intestinal and diffuse subtypes on a morphologic basis, supported by corollary evidence of differences at the pathogenetic and molecular levels. Chronic atrophic gastritis with intestinal metaplasia is a common precursor lesion for the intestinal type of carcinoma. To identify early molecular changes, in this study we have examined 13 surgical specimens both for the expression of E-cadherin, p53 and beta-catenin by immunohistochemistry and for methylation of the CDH1 promoter (E-cadherin) by bisulfite genomic sequencing of laser capture microdissected samples. Each specimen examined contained areas of normal (nonmetaplastic) gastric mucosa, as well as areas of intestinal metaplasia and/or carcinoma. Reduced or absent E-cadherin and partial to complete methylation of one to multiple CpG sites examined in the CDH1 promoter were observed in all of the metaplasia samples. Thus, the methylation status of the CDH1 promoter and expression of E-cadherin together provide strong evidence that loss of E-cadherin is an early event in intestinal type gastric carcinogenesis. In contrast, expression of p53, assumed to be mutant p53, was generally not detected (except for isolated cells) until the carcinoma stage in tissues from these patients. These results suggest that mutation of p53 is a late event in intestinal type gastric cancer. The level of beta-catenin expression did not appear to change between normal, metaplastic and carcinoma cells of intestinal type, and no nuclear staining was visible in any of the tissues. These results suggest that the Wnt signaling pathway is not upregulated in this type of cancer.
Collapse
|
|
37
|
Tamura G, Sato K, Akiyama S, Tsuchiya T, Endoh Y, Usuba O, Kimura W, Nishizuka S, Motoyama T. Molecular characterization of undifferentiated-type gastric carcinoma. J Transl Med 2001; 81:593-8. [PMID: 11304579 DOI: 10.1038/labinvest.3780268] [Citation(s) in RCA: 58] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
As the great majority of gastric cancers develop histologically differentiated, and a significant proportion of differentiated-type carcinomas progress to become undifferentiated, both histological types are likely to share several common genetic abnormalities, such as p53 mutations at advanced stages. However, a subset of gastric cancers develop as undifferentiated carcinomas, including signet-ring cell carcinoma and poorly differentiated adenocarcinoma, and the molecular pathogenesis of this tumor type remains largely unknown. To characterize the molecular features of undifferentiated-type gastric carcinomas that developed as undifferentiated-type, we examined for p53, APC, and epithelial (E)-cadherin gene mutations, microsatellite alterations including loss of heterozygosity (LOH) and microsatellite instability (MSI), and hypermethylation of the E-cadherin gene promoter in 26 early undifferentiated gastric carcinomas, consisting of 14 signet-ring cell carcinomas and 12 poorly differentiated adenocarcinomas. E-cadherin expression was evaluated immunohistochemically. p53 mutations were detected in only one poorly differentiated adenocarcinoma sample (3.8%; 1/26), whereas no APC or E-cadherin mutations were found. LOH was present only at D8S261 on the short arm of chromosome 8 in 2 of 14 (14%) informative tumors, both of which were poorly differentiated adenocarcinomas, and MSI was not observed in any of the tumors. No signet-ring cell carcinomas have been found to carry gene mutations or microsatellite alterations. In contrast, hypermethylation of the E-cadherin promoter occurred in 69% (18/26) of the tumors; 57% (8/14) of signet-ring cell carcinomas, and 83% (10/12) of poorly differentiated adenocarcinomas, and was significantly associated with loss or reduced expression of E-cadherin. Thus, whereas tumor suppressor gene mutation, LOH, and MSI were less common in undifferentiated-type early gastric carcinomas, epigenetic inactivation of E-cadherin via promoter hypermethylation may be an early critical event in the development of undifferentiated tumors.
Collapse
Affiliation(s)
- G Tamura
- Department of Pathology, Yamagata University School of Medicine, Yamagata, Japan.
| | | | | | | | | | | | | | | | | |
Collapse
|
|
38
|
Ohene-Abuakwa Y, Noda M, Perenyi M, Kobayashi N, Kashima K, Hattori T, Pignatelli M. Expression of the E-cadherin/catenin (alpha-, beta-, and gamma-) complex correlates with the macroscopic appearance of early gastric cancer. J Pathol 2000; 192:433-9. [PMID: 11113859 DOI: 10.1002/1096-9896(2000)9999:9999<::aid-path723>3.0.co;2-v] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
E-cadherin and its associated cytoplasmic proteins, alpha-, beta-, and gamma-catenins, play an essential role in the control of epithelial differentiation. We have previously shown that loss or down-regulation of E-cadherin/catenin correlates with poor survival in advanced gastric adenocarcinoma. The aim of this study was to assess the expression of E-cadherin and catenins in early gastric cancers (EGCs). Immunohistochemical staining for E-cadherin and alpha-, beta-, and gamma-catenins was performed on 41 paraffin-embedded gastrectomy specimens of EGC using an indirect immunoperoxidase technique. The pattern of expression and cellular localization of the E-cadherin/catenin complex in tumour cells were correlated with the macroscopic appearance of the tumour according to the Japanese Endoscopic Society classification. The tumours were classified as follows: three type I (protruding) and 38 type II (superficial), of which ten were type IIa (elevated), one was type IIb (flat), and 27 were type IIc (depressed). E-cadherin and alpha-, beta-, and gamma-catenins were expressed at the cell-cell junctions in normal mucosa. Forty out of 41 tumours showed abnormal expression (loss of membranous immunoreactivity and/or nuclear staining) of at least one component of the E-cadherin catenin complex. Loss of E-cadherin immunoreactivity was more frequently seen in type IIb (1/1, 100%) and type IIc (27/27, 100%) than in type I (1/3, 33%) and type IIa (1/10, 10%) (p<0.01). Abnormal expression of E-cadherin and alpha-catenin was more frequently seen in diffuse-type than in intestinal type tumours (p<0.05). Abnormal immunoreactivity of beta- and gamma-catenin, including nuclear localization, was observed in 34% and 7.3% of tumours, respectively, but there was no significant correlation with tumour type or endoscopic appearance. In conclusion, abnormal expression of the E-cadherin/catenin complex occurs in EGC and seems to correlate with macroscopic appearances.
Collapse
Affiliation(s)
- Y Ohene-Abuakwa
- Division of Histopathology, Department of Pathology and Microbiology, University of Bristol, Bristol Royal Infirmary, Bristol, UK
| | | | | | | | | | | | | |
Collapse
|
|
39
|
|
|
40
|
Abstract
BACKGROUND The E-cadherin-catenin complex plays a crucial role in epithelial cell-cell adhesion and in the maintenance of tissue architecture. Perturbation in the expression or function of this complex results in loss of intercellular adhesion, with possible consequent cell transformation and tumour progression. Recently, much progress has been made in understanding the interaction between the different components of this protein complex and how this cell-cell adhesion complex is modulated in cancer cells. METHODS This is an update of the role of the E-cadherin-catenin complex in human cancers. It emphasizes new features and the possible role of the complex in clinical practice, discussed in the light of 165 references obtained from the Medline database from 1995 to 1999. RESULTS More evidence is now appearing to suggest that disturbance in protein-protein interaction in the E-cadherin-catenin adhesion complex is one of the main events in the early and late steps of cancer development. An inverse correlation is found between expression of the E-cadherin-catenin complex and the invasive behaviour of tumour cells. Therefore, E-cadherin-catenin may become a significant prognostic marker for tumour behaviour. Besides its role in establishing tight cell-cell adhesion, beta- catenin plays a major role in cell signalling and promotion of neoplastic growth. This suggests its dual role as a tumour suppressor and as an oncogene in human cancers. CONCLUSION Recent developments show that the E-cadherin-catenin complex is more than a 'sticky molecular complex'. Further studies may yield greater insight into the early molecular interactions critical to the initiation and progression of tumours. This should aid the development of novel strategies for both prevention and treatment of cancer.
Collapse
Affiliation(s)
- B P Wijnhoven
- Departments of Surgery and Pathology, Erasmus University Medical Centre, Rotterdam, The Netherlands
| | | | | |
Collapse
|
|
41
|
|