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Xia M, Xie Y, Zan L, Reddy S, Tan C, Li J, Zhou D, Tan D. Membranous staining of β-catenin and E-cadherin expression in patients with gastric cancer. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2017; 10:8980-8990. [PMID: 31966768 PMCID: PMC6965369] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 03/16/2017] [Accepted: 04/21/2017] [Indexed: 06/10/2023]
Abstract
BACKGROUND β-catenin and E-cadherin are adhesion molecules that promote metastatic potential through epithelial-mesenchymal transition (EMT). Although they have not been extensively studied in gastric cancers, they represent potential testable prognostic markers. METHODS We explored the association between the immunohistochemical expression of these markers and clinicopathologic parameters by retrospectively reviewing 205 cases of gastric cancer from tissue microarrays (TMA). A method was developed to evaluate for membranous staining of β-catenin and E-cadherin using grading criteria that characterized both the intensity of staining and the percentage of cells with loss of staining. RESULTS Weak membranous expression of E-cadherin and β-catenin were associated with worse overall survival (p<0.05). Abnormal expression of E-cadherin and β-catenin were significantly associated with each other (p<0.01). Loss of and/or weak membranous staining for both E-cadherin and β-catenin was significantly associated with advanced cancer stage T2-T4 (versus stage T1, p<0.05) and tumors that are negative for H pylori infection (p<0.05). In addition, loss of and/or weak membranous staining for β-catenin was significantly associated with poorly differentiated tumors (p<0.05), diffuse Lauren-type gastric tissue (p=0.02), and tumors with a significantly higher rate of lymphovascular invasion (p=0.02). CONCLUSION Loss of/weak membranous expression of both E-cadherin and β-catenin was associated with poorer overall survival rates and clinicopathologic parameters that indicated an aggressive clinical behavior. β-catenin shows significant associations with more clinical parameters, making it a better biomarker than E-cadherin. In our multivariate analysis, weak intensity of staining of β-catenin was an independent prognostic factor for survival and may be a useful immunohistochemical prognostic marker for patients with gastric cancer.
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Affiliation(s)
- Michelle Xia
- Department of Pathology, University of PittsburghPA, USA
| | - Yan Xie
- Department of Pathology, University of PittsburghPA, USA
| | - Likun Zan
- Departments of Pathology and Gastrointestinal Medical Oncology, MD Anderson Cancer CenterHouston, TX, USA
| | - Sumanth Reddy
- Uniniversity of Texas Southwestern Medical CenterDallas, TX, USA
| | - Christina Tan
- Rice University, Texas Medical CenterHouston, TX, USA
| | - Jing Li
- Department of Pathology, Kingmed Diagnostics, Guangzhou Medical UniversityGuangzhou, China
| | - David Zhou
- Departments of Medicine and Pathology, University of RochesterRochester, NY, USA
| | - Dongfeng Tan
- Departments of Pathology and Gastrointestinal Medical Oncology, MD Anderson Cancer CenterHouston, TX, USA
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Machado JC, Carneiro F, Beck S, Rossi S, Lopes J, Taveira-Gomes A, Cardoso-Oliveira M. E-Cadherin Expression Is Correlated with the Isolated Cell/Diffuse Histotype and with Features of Biological Aggressiveness of Gastric Carcinoma. Int J Surg Pathol 2016. [DOI: 10.1177/106689699800600302] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
We studied the pattern of immunohistochemical expression of E-cadherin in a series of 50 gastric carcinomas, aiming to analyze its relationship with histotype and features of biological aggressiveness of the tumors and survival of the patients. Abnormal E-cadherin expression was significantly (p=.0007) higher in diffuse/isolated-cell type carcinomas than in intestinal/glandular carcinomas. In mixed carcinomas abnormal E-cadherin expression in the diffuse/isolated-cell-type component (94.4%) was significantly (p=.007) higher than in intestinal/glandular component (55.6%). Significant relationships were observed between abnormal E-cadherin expression and nodal metastases (p=.004) and pTNM stages (p=.05). Survival of patients with tumors displaying abnormal E-cadherin expression was worse than that of patients with tumors presenting normal expression, though not attaining the threshold of statistical significance (p=.l9). We conclude that abnormal E-cadherin expression is correlated with diffuse/isolated-cell histotype and features of biological aggressiveness of gastric carcinoma.
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Affiliation(s)
- José C. Machado
- Institute of Molecular Pathology and Immunology of University of Porto (IPATIMUP), Medical Faculty, Porto, Portugal; IPATIMUP, Rua Roberto Frias, s/n, 4200 Porto, Portugal
| | - Fáitima Carneiro
- Institute of Molecular Pathology and Immunology of University of Porto (IPATIMUP), Medical Faculty, Porto, Portugal
| | - Stefanie Beck
- Institute for Anthropology and Human Genetics, University of Tübingen, Tübingen, Germany
| | - Simone Rossi
- Health Secretary of the State of Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Joanne Lopes
- Department of Pathology, H. S. Joãao, Medical Faculty, Porto, Portugal
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Qiu ZX, Zhao S, Li L, Li WM. Prognostic value and clinicopathological significance of epithelial cadherin expression in non-small cell lung cancer. Thorac Cancer 2015; 6:589-96. [PMID: 26445607 PMCID: PMC4567004 DOI: 10.1111/1759-7714.12227] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2014] [Accepted: 12/11/2014] [Indexed: 02/05/2023] Open
Abstract
Background Epithelial cadherin (E-cadherin), a calcium-dependent cell-cell adhesion molecule, as an important adhesion and signaling pathway mediator plays key roles in the maintenance of tissue integrity. However, the available results of E-cadherin expression and its prognostic value on non-small cell lung cancer (NSCLC) remain controversial. Therefore, a meta-analysis of published studies investigating the prognostic value of E-cadherin expression and its association with clinicopathological characteristics with NSCLC was performed. Methods A literature search via PubMed, EMBASE, and MEDLINE (Ovid) databases was conducted. Data from eligible studies were extracted. Statistical analysis was performed using STATA 12.0. Results A total of 2412 patients from 15 studies were included in the meta-analysis. The results showed that the pooled hazard ratio (HR) for overall survival was 0.55 (95% confidence interval [CI]: 0.44–0.69) by univariate analysis and 0.68 (95% CI: 0.43–1.08) by multivariate analysis. In addition, the results showed a significant association between E-cadherin expression and the presence of lymph node metastasis (odds ratio = 0.37, 95% CI=0.05–0.69, P = 0.001). Conclusion Our study showed that positive expression of E-cadherin was associated with a favorable prognosis in patients with NSCLC, and might act as an inhibition factor of metastasis. However, adequately designed prospective studies are required to confirm this finding.
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Affiliation(s)
- Zhi-Xin Qiu
- Department of Respiratory Medicine, West China Hospital, Sichuan University Chengdu, China
| | - Shuang Zhao
- Department of Respiratory Medicine, West China Hospital, Sichuan University Chengdu, China
| | - Lei Li
- Department of Respiratory Medicine, West China Hospital, Sichuan University Chengdu, China
| | - Wei-Min Li
- Department of Respiratory Medicine, West China Hospital, Sichuan University Chengdu, China
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4
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Koh YW, Jun SY, Kim KR. Prognostic significance of single isolated cells with decreased E-cadherin expression in pseudomyxoma peritonei. Pathol Int 2014; 64:164-72. [PMID: 24750186 DOI: 10.1111/pin.12157] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2013] [Accepted: 03/17/2014] [Indexed: 12/17/2022]
Abstract
Pseudomyxoma peritonei (PMP) cases can be classified into the prognosis-related subtypes of disseminated peritoneal adenomucinosis (DPAM) and peritoneal mucinous carcinomatosis (PMCA). To investigate the mechanisms of mucinous invasion and the differing prognoses of these two subtypes, we examined the expression levels of proteins involved in cellular adhesion and invasion, including E-cadherin, vimentin, β-catenin, and S100A4, in single isolated tumor cells (SICs) and cohesive cellular strips within mucin pools isolated from DPAM (n = 31) and PMCA (n = 21) patients. In both PMCA and DPAM cases, SICs showed a complete loss of E-cadherin expression, whereas cells in cohesive cellular clusters retained E-cadherin expression. The frequency of high numbers of SICs (>8) in PMCA cases was significantly greater than that in DPAM cases (86% and 26%, respectively) and was correlated with poor progression-free survival (P = 0.019) in a univariate analysis. In both PMP subtypes, strong vimentin expression was identified in most of the SICs but not the cohesive cellular strips. The relatively slow progression of DPAM may be attributable to the smaller number of SICs that lack E-cadherin expression and have increased vimentin expression, whereas the rapid progression of PMCA may be due to larger numbers of these SICs.
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Affiliation(s)
- Young Wha Koh
- Department of Pathology, Ajou University School of Medicine, Suwon, South Korea
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5
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Mahu C, Purcarea AP, Gheorghe CM, Purcarea MR. Molecular events in gastric carcinogenesis. J Med Life 2014; 7:375-8. [PMID: 25408758 PMCID: PMC4233442] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2014] [Accepted: 06/29/2014] [Indexed: 11/24/2022] Open
Abstract
Gastric cancer represents an important problem for the public health, being one of the main causes of mortality. At present, it represents the second cause of mortality due to cancer, after the bronchopulmonary cancer in men and the fourth cause of mortality in women. Important progresses have been made in the last couple of years in determining the neoplastic etiopathogenesis, but it cannot be affirmed that the genetic mutations chain, which leads to the appearance of the malignant cell, has been fully understood.
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Affiliation(s)
- C Mahu
- "Prof. Dr. D. Gerota" Ministry of Internal Affairs Emergency Hospital, Bucharest, Romania
| | - A P Purcarea
- "Carol Davila" University of Medicine and Pharmacy, Bucharest, Romania
| | - C M Gheorghe
- "Carol Davila" University of Medicine and Pharmacy, Bucharest, Romania
| | - M R Purcarea
- "Dr. Carol Davila" Clinical Nephrology Hospital, Bucharest, Romania
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Lim MG, Adsay NV, Grignon DJ, Osunkoya AO. E-cadherin expression in plasmacytoid, signet ring cell and micropapillary variants of urothelial carcinoma: comparison with usual-type high-grade urothelial carcinoma. Mod Pathol 2011; 24:241-7. [PMID: 20818341 DOI: 10.1038/modpathol.2010.187] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Loss of E-cadherin expression has been linked to the invasive phenotypes of a variety of neoplasms, including lobular breast cancer. The expression of E-cadherin in variants of urothelial carcinoma relative to usual-type urothelial carcinoma, maximum depth of invasion and angiolymphatic invasion has not been well characterized. A total of eight cases of micropapillary urothelial carcinoma, four cases of plasmacytoid urothelial carcinoma, two cases of urothelial carcinoma with signet ring cell differentiation and two cases of urothelial carcinoma with mixed plasmacytoid and signet ring cell differentiation, all obtained from cystectomy/cystoprostatectomy cases, were identified. In all nine cases of usual-type invasive and noninvasive high-grade urothelial carcinoma were also included in the study. Immunohistochemical staining of E-cadherin was performed in all cases. Pathological parameters including depth of invasion and presence of angiolymphatic invasion were documented. Maximum depth of invasion: In micropapillary urothelial carcinoma, extravesical extension was seen in three of eight cases; muscularis propria invasion in four of eight cases; and lamina propria invasion in one of eight cases. In plasmacytoid urothelial carcinoma, extravesical extension was observed in two of four cases, and muscularis propria invasion and lamina propria invasion in one of four cases each. In urothelial carcinoma with signet ring cell differentiation, extravesical extension and muscularis propria invasion was seen in one of two cases each. In urothelial carcinoma with mixed plasmacytoid and signet ring cell differentiation, muscularis propria invasion and lamina propria invasion was observed in one of two cases each. In usual-type high-grade urothelial carcinoma, extravesical extension was seen in six of nine cases and noninvasive in three of nine cases. In angiolymphatic invasion, micropapillary urothelial carcinoma was observed in eight of eight cases; plasmacytoid urothelial carcinoma in two of four cases; urothelial carcinoma with signet ring cell differentiation in one of two cases; and urothelial carcinoma with mixed plasmacytoid and signet ring cell differentiation in one of two cases. Usual-type high-grade urothelial carcinoma was seen in six of nine cases. E-cadherin expression: All eight cases of micropapillary urothelial carcinoma were positive for E-cadherin in the micropapillary component and adjacent usual-type urothelial carcinoma. The four cases of plasmacytoid urothelial carcinoma, two cases of urothelial carcinoma with signet ring cell differentiation and two cases of urothelial carcinoma with mixed plasmacytoid and signet ring cell differentiation were all negative for E-cadherin. All nine additional cases of usual-type high-grade urothelial carcinoma were diffusely positive for E-cadherin. E-cadherin is diffusely positive in usual-type urothelial carcinoma and micropapillary urothelial carcinoma, irrespective of pathological stage and angiolymphatic invasion. Loss of E-cadherin expression may be a marker of plasmacytoid and signet ring cell differentiation in urothelial carcinoma.
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Affiliation(s)
- Matthew G Lim
- Department of Pathology, Emory University School of Medicine, Atlanta, GA, USA
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Pagaki E, Patsouris E, Gonidi M, Athanassiadou AM, Maurikakis M, Athanassiades P, Chelidonis G, Athanassiadou P. The value of E-cadherin/beta-catenin expression in imprints of NCSLC: relationship with clinicopathological factors. Diagn Cytopathol 2010; 38:419-24. [PMID: 20474081 DOI: 10.1002/dc.21188] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Metastasis is specific for malignant tumors and its control is one of the most important problems in the design of therapies for cancer patients. Loss or reduction of E-cadherin expression and/or beta-catenin expression plays a casual role in tumor progression and metastasis and is associated with poor prognosis. The purpose of the study is to investigate the expression of E-cadherin and beta-catenin and their significance as independent prognostic markers in imprints of resected nonsmall cell lung cancer (NSCLC). Imprint smears from 70 patients who underwent surgical lung resection for primary carcinoma were studied. As control group was used imprints of physiological tissues. Histologically 47 (67.1%) of the tumors were squamous cell carcinomas and 23 (32.9%) were adenocarcinomas. Tumors stage was I in 29 (41.4%), II in 13 (18.6%), III in 24 (34.3%) and IV in 4 (5.7%). Positive expression for E-cadherin was observed in 44.29% of malignant smears vs 85.71% for control group (P = 0.011). For beta-catenin, positive expression was observed in 42.86% malignant cases vs 85.71% for control group (P = 0.008). Positive expression of E-cadherin and beta-catenin was observed in moderate and well differentiated tumors (P < 0.0001 for both respectively). Positive E-cadherin and beta-catenin expression was observed in 70.6% and 76.5% of the cases with negative lymphnode metastasis (P < 0.0001 for both respectively). There was no statistically significant association between histological type, tumor stage, pleural invasion, tumor size (P > 0.05 for all) and E-cadherin/beta-catenin expression.Reduced E-cadherin or beta-catenin negative expression relates to dedifferentiation and progression of NSCLC.
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8
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Collagen Type I may Influence the Expression of E-Cadherin and Beta-catenin in Carcinoma Ex-pleomorphic Adenoma. Appl Immunohistochem Mol Morphol 2009; 17:312-8. [DOI: 10.1097/pai.0b013e3181946ea6] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Abstract
Even though liver metastasis accounts for the vast majority of cancer deaths in patients with colorectal cancer (CRC), fundamental questions about the molecular and cellular mechanisms of liver metastasis still remain unanswered. Determination of gene expression profiles by microarray technology has improved our knowledge of CRC molecular pathways. However, defined gene signatures are highly variable among studies. Expression profiles and molecular markers have been specifically linked to liver metastases mechanistic paths in CRC. However, to date, none of the identified signatures or molecular markers has been successfully validated as a diagnostic or prognostic tool applicable to routine clinical practice. To obtain a genetic signature for liver metastasis in CRC, measures to improve reproducibility, to increase consistency, and to validate results need to be implemented. Alternatives to expression profiling with microarray technology are continuing to be used. In the recent past, many genes codifying for proteins that are directly or indirectly involved in adhesion, invasion, angiogenesis, survival and cell growth have been linked to mechanisms of liver metastases in CRC.
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Jäger T, Szarvas T, vom Dorp F, Börgermann C, Schenck M, Schmid KW, Rübben H. Einsatz der Siliziumchiptechnologie zur Detektion von Tumormarkern auf Proteinbasis beim Harnblasenkarzinom. Urologe A 2007; 46:1152-6. [PMID: 17593336 DOI: 10.1007/s00120-007-1429-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
The protein structure of human tumor tissue has a significant influence on the molecular attributes. It was demonstrated that the individual prognosis of tumor patients is among other things dependent on molecular tumor tissue characteristics.A promising marker is E-cadherin, an adhesion glycoprotein which plays a central role in the mediation of cell-cell contacts. Aberrant E-cadherin expressions were described in several tumors such as in bladder cancer. This was also found to be correlated with tumor invasion and survival. There are hardly any fast, quantitative and easily automated protein assays in everyday practice which can analyze several markers at the same time. With silicon chip technology we have a new detection and measurement method which makes it possible to give a quantitative analysis of numerous different proteins in tissue, urine, or serum in a few minutes.
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Affiliation(s)
- T Jäger
- Klinik für Urologie, Universitätsklinikum, Hufelandstrasse 55, 45147 Essen.
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Erdemir F, Ozcan F, Kilicaslan I, Parlaktas BS, Uluocak N, Gokce O. The relationship between the expression of E-cadherin and tumor recurrence and progression in high-grade stage T1 bladder urothelial carcinoma. Int Urol Nephrol 2007; 39:1031-7. [PMID: 17340210 DOI: 10.1007/s11255-006-9159-5] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2006] [Accepted: 11/21/2006] [Indexed: 01/08/2023]
Abstract
OBJECTIVE To evaluate the relationship between the expression of E-cadherin (E-CD) and tumor recurrence and progression in patients with high-grade stage T1 urothelial carcinoma of bladder. METHODS Fifty-two patients who had primary high-grade stage T1 urothelial carcinoma were enrolled to the study. The pathologic specimens of patients were evaluated and staged as T1a and T1b according to muscularis mucosae involvement by the tumor. The immunohistochemical demonstration of E-CD was accomplished by using immunoperoxidase method and all the specimens were examined under light microscope for E-CD level. RESULTS The mean age of the patients was 64.0 +/- 7.7 (range 36-81) years. The mean follow-up period was 56.4 +/- 19.4 (range 14-84) months. Among 52 patients, 27 (52%) of them were stage T1b and 25 (48%) were T1a tumors. The recurrence rates for T1a and T1b groups were 52% (n = 13) and 92.6% (n = 25), respectively (P < 0.05). The expression of E-CD was homogenous in 52% of pT1a and 14.8% of T1b tumors (P < 0.05). In T1a group with recurrence, homogeneous E-CD staining ratio was 30.7% (n = 4/13), but it was 75% (n = 9/12) in T1a patients without recurrence (P < 0.05). In T1b group with recurrence, the homogenous expression of E-CD was 12% (n = 3/25) and the expression of E-CD was heterogenous in 88% (n = 22/25) of them (P < 0.05). In T1a group, progression of the disease was detected in 28% (n = 7/25) of the patients, but disease progression was seen in 55.5% (n = 15/27) of T1b group patients (P < 0.05). In T1a group with progression, heterogeneous E-CD staining ratio was 85.7% (n = 6/7), but it was 80% (n = 12/15) in T1b patients with progression. The effects of tumor number, tumor size and carcinoma in situ presence on recurrence were evaluated within each group. It was determined that parameters such as tumor number and tumor size had no significant effect on recurrence of the groups. The mean survival rates were statistically different between the groups. On multivariate analysis only E-cadherin expression (P = 0.012, odds ratio 6.291, 95% confidence interval for odds ratio 1.303-4.72) and tumor stage (P = 0.003, odds ratio 11.58, 95% confidence interval for odds ratio 2.446-8.542) remained independently significant as predictors of recurrence. CONCLUSION E-CD expression was decreased in pathologic specimens of bladder tumor patients with muscularis mucosae involvement and this condition correlated well with tumor recurrence.
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Affiliation(s)
- Fikret Erdemir
- Yeşilirmak M. Bosna C. 3. Sok., No:7, Mollaoğullari Apt. K:2, D;3, Merkez, Tokat, 60100, Turkey.
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12
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Bebb JR, Leach L, Zaitoun A, Hand N, Letley DP, Thomas R, Atherton JC. Effects of Helicobacter pylori on the cadherin-catenin complex. J Clin Pathol 2006; 59:1261-6. [PMID: 16679349 PMCID: PMC1860537 DOI: 10.1136/jcp.2006.036772] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND The cadherin-catenin complex is the key component of the adherens junction in epithelial cells, and changes in this complex are implicated in gastric adenocarcinoma. Germline mutations in E-cadherin have been described in diffuse-type gastric adenocarcinoma. Helicobacter pylori infection is the first stage in gastric carcinogenesis. AIMS To determine whether H pylori was associated with changes in the complex, and whether this was affected by virulence of the strain. METHODS Epithelial cell lines were cultured with H pylori using the wild-type pathogenic and non-pathogenic strains and CagE null and VacA null isogenic mutants. Gastric biopsy specimens at endoscopy were obtained from patients with (n = 17) and without (n = 15) H pylori infection, and E-cadherin and beta-catenin expression was assessed by immunohistochemistry. H pylori was typed by polymerase chain reaction from these patients for CagE and VacA. RESULTS In vitro studies showed that coculture with a pathogenic strain of H pylori led to disruption of epithelial junctional beta-catenin expression, but without evidence of nuclear translocation or signalling. This effect was independent of a functional Cag pathogenicity island and vacuolating activity, but dependent on live bacteria. No marked differences in beta-catenin or E-cadherin expression were seen in gastric biopsy specimens in patients with and without H pylori infection. CONCLUSION Acute H pylori infection disrupts junctional beta-catenin in vitro, but chronic infection by H pylori has no effect on E-cadherin and beta-catenin expression, as seen in gastric biopsy specimens at the initial gastritis stage of the proposed Correa pathway of gastric carcinogenesis. A later effect at the later stages of atrophy or intestinal metaplasia cannot be ruled out.
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Affiliation(s)
- J R Bebb
- Wolfson Centre for Digestive Diseases and Institute of Infections, Inflammation and Immunity, University Hospital Nottingham, Nottingham, UK.
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Liu YC, Shen CY, Wu HS, Hsieh TY, Chan DC, Chen CJ, Yu JC, Yu CP, Harn HJ, Chen PJ, Hsieh CB, Chen TW, Hsu HM. Mechanisms inactivating the gene for E-cadherin in sporadic gastric carcinomas. World J Gastroenterol 2006; 12:2168-73. [PMID: 16610016 PMCID: PMC4087641 DOI: 10.3748/wjg.v12.i14.2168] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.1] [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 study the role of CDH1/E-cadherin (E-cad) gene alteration profiles including mutation, loss of heterozygosity (LOH), promoter polymorphism and hypermethylation in mechanisms of CDH1 inactivation in gastric carcinoma (GC).
METHODS: Specimens were collected surgically from 70 patients with GC. Allelotyping PCR and detection of LOH, denaturing high pressure liquid chromatography and DNA sequencing, restriction fragment length polymorphism analysis, methylation specific PCR, and immunohistochemical staining were used.
RESULTS: Promoter polymorphism was not a major mechanism of E-cad inactivation. Only one truncating mutation was found in a diffuse type tumor (3%). Both LOH and promoter hypermethylation were major mechanisms of E-cad inactivation, but interestingly, there was a negative association between the fraction of allelic loss (LOH) in tumors and hypermethylation of CDH1. Therefore LOH and hypermethylation were two different tumorigenic pathways involved in GC.
CONCLUSION: Given the findings that somatic mutation was extremely low and the relationship between LOH and hypermethylation was inverse, any two combinations of these three factors cannot fulfill the classical two-hit hypothesis of CDH1 inactivation. Thus, other mechanisms operating at the transcriptional level or at the post-translational level might be required to induce E-cadherin inactivation.
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Affiliation(s)
- Yao-Chi Liu
- Division of General Surgery, Tri-Service General Hospital, No. 325, Sec 2, Cheng-Kung Road, Taipei, Taiwan, China.
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Shen G, Xu C, Hu R, Jain MR, Gopalkrishnan A, Nair S, Huang MT, Chan JY, Kong ANT. Modulation of nuclear factor E2-related factor 2-mediated gene expression in mice liver and small intestine by cancer chemopreventive agent curcumin. Mol Cancer Ther 2006; 5:39-51. [PMID: 16432161 DOI: 10.1158/1535-7163.mct-05-0293] [Citation(s) in RCA: 117] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Curcumin has been shown to prevent and inhibit carcinogen-induced tumorigenesis in different organs of rodent carcinogenesis models. Our objective is to study global gene expression profiles elicited by curcumin in mouse liver and small intestine as well as to identify curcumin-regulated nuclear factor E2-related factor 2 (Nrf2)-dependent genes. Wild-type C57BL/6J and Nrf2 knockout C57BL/6J/Nrf2(-/-) mice were given a single oral dose of curcumin at 1,000 mg/kg. Liver and small intestine were collected at 3 and 12 hours after treatments. Total RNA was extracted and analyzed using Affymetrix (Santa Clara, CA) mouse genome 430 array (45K) and GeneSpring 6.1 software (Silicon Genetics, Redwood City, CA). Genes that were induced or suppressed >2-fold by curcumin treatments compared with vehicle in wild-type mice but not in knockout mice were filtered using GeneSpring software and regarded as Nrf2-dependent genes. Among those well-defined genes, 822 (664 induced and 158 suppressed) and 222 (154 induced and 68 suppressed) were curcumin-regulated Nrf2-dependent genes identified in the liver and small intestine, respectively. Based on their biological functions, these genes can be classified into the category of ubiquitination and proteolysis, electron transport, detoxification, transport, apoptosis and cell cycle control, cell adhesion, kinase and phosphatase, and transcription factor. Many phase II detoxification/antioxidant enzyme genes, which are regulated by Nrf2, are among the identified genes. The identification of curcumin-regulated Nrf2-dependent genes not only provides potential novel insights into the biological effects of curcumin on global gene expression and chemoprevention but also points to the potential role of Nrf2 in these processes.
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Affiliation(s)
- Guoxiang Shen
- Graduate Program in Pharmaceutical Science, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, 08854, USA
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Takayama T, Miyanishi K, Hayashi T, Sato Y, Niitsu Y. Colorectal cancer: genetics of development and metastasis. J Gastroenterol 2006; 41:185-92. [PMID: 16699851 DOI: 10.1007/s00535-006-1801-6] [Citation(s) in RCA: 166] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2006] [Accepted: 03/06/2006] [Indexed: 02/04/2023]
Abstract
It has been well documented that there are two major pathways in colorectal carcinogenesis. One is the chromosomal instability pathway (adenoma-carcinoma sequence), which is characterized by allelic losses on chromosome 5q (APC), 17p (p53), and 18q (DCC/SMAD4), and the other is a pathway that involves microsatellite instability. Recent progress in molecular biology, however, has shown that colorectal carcinogenesis is not necessarily clearly divided into these two pathways, but is in fact more complicated. Other routes, including the transforming growth factor-beta/SMAD pathway, the serrated pathway, and the epigenetic pathway, have been reported. Cross talk among these pathways has also been reported. In the invasion and metastasis steps of colorectal cancers, many more genes have now been identified as being involved in proteolysis, adhesion, angiogenesis, and cell growth. Recently accumulated evidence indicates that colorectal cancer is a genetically heterogeneous and complicated disease.
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Affiliation(s)
- Tetsuji Takayama
- Fourth Department of Internal Medicine, Sapporo Medical University, School of Medicine, South-1, West-16, Sapporo, 060-8543, Japan
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16
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Liu YC, Shen CY, Wu HS, Chan DC, Chen CJ, Yu JC, Yu CP, Harn HJ, Shyu RY, Shih YL, Hsieh CB, Hsu HM. Helicobacter pylori infection in relation to E-cadherin gene promoter polymorphism and hypermethylation in sporadic gastric carcinomas. World J Gastroenterol 2005; 11:5174-9. [PMID: 16127748 PMCID: PMC4320391 DOI: 10.3748/wjg.v11.i33.5174] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [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 study Helicobacter pylori (H pylori) infection in relation to E-cadherin (E-cad) promoter polymorphism and hypermethylation in GCs.
METHODS: Specimens were taken from representative cancerous lesions and adjacent non-cancerous epithelia of 67 resected GCs. H pylori was detected by real-time PCR of the cagA gene from non-neoplastic epithelium. E-cad promoter polymorphism and hypermethylation were determined by restriction fragment length polymorphism analysis and methylation-specific PCR, respectively. Expression of E-cad protein was determined by immunohistochemistry.
RESULTS: H pylori was found in 57% of patients with GC. H pylori infection was more frequently found in tumors with the -160C/C genotype than those with the -160C/A and -160A/A genotypes (74% vs 47%, P = 0.02). H pylori infection was associated with E-cad methylation in non-neoplastic epithelium; however, no significant difference in H pylori was observed between methylated and unmethylated cancerous lesions.
CONCLUSION: Patients with the -160C/C genotype might require H pylori infection to promote the inactivation of CDH1, suggesting that H pylori infection might affect GC in an initial stage because polymorphism is germ line. Mechanism of hypermethylation of CDH1 promoter in GC is complex, and H pylori infection might affect it in an initial stage.
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Affiliation(s)
- Yao-Chi Liu
- Division of General Surgery, Tri-Service General Hospital, No. 325, Sec. 2, Cheng-Kung Road, Neihu 114, Taipei, Taiwan, China.
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17
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Shen G, Xu C, Hu R, Jain MR, Nair S, Lin W, Yang CS, Chan JY, Kong ANT. Comparison of (-)-epigallocatechin-3-gallate elicited liver and small intestine gene expression profiles between C57BL/6J mice and C57BL/6J/Nrf2 (-/-) mice. Pharm Res 2005; 22:1805-20. [PMID: 16132347 DOI: 10.1007/s11095-005-7546-8] [Citation(s) in RCA: 112] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2005] [Accepted: 07/18/2005] [Indexed: 12/17/2022]
Abstract
PURPOSE This study was conducted to study global gene expression profiles elicited by (-)-epigallocatechin-3-gallate (EGCG) in mouse liver and small intestine, as well as to identify EGCG-regulated Nrf2-dependent genes. METHODS C57BL/6J and C57BL/6J/Nrf2(-/-) mice were given an oral dose of EGCG at 200 mg/kg or treated with vehicle. Both liver and small intestine were collected 3 h and 12 h after treatment. Total RNA was extracted from the tissues and gene expression profiles were analyzed using Affymetrix mouse genome 430 2.0 array and GeneSpring 6.1 software. Microarray data were validated using quantitative real-time reverse transcription-PCR chain reaction analysis. RESULTS Genes that were either induced or suppressed more than two fold by EGCG treatment compared with vehicle treatment in the same genotype group were filtered using the GeneSpring software. Among these well-defined genes, 671 EGCG-regulated Nrf2-dependent genes and 256 EGCG-regulated Nrf2-independent genes were identified in liver, whereas 228 EGCG-regulated Nrf2-dependent genes and 98 EGCG-regulated Nrf2-independent genes were identified in the small intestine. Based on their biological functions, these genes mainly fall into the category of ubiquitination and proteolysis, electron transport, detoxification, transport, cell growth and apoptosis, cell adhesion, kinase and phosphatases, and transcription factors. CONCLUSIONS Genes expressed in mouse liver are more responsive to oral treatment of EGCG than those expressed in small intestine. EGCG could regulate many genes in both organs in an Nrf2-dependent manner. The identification of genes related to detoxification, transport, cell growth and apoptosis, cell adhesion, kinase, and transcription regulated by EGCG not only provide potential novel insight into the effect of EGCG on global gene expression and chemopreventive effects, but also point to the potential role of Nrf2 in these processes.
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Affiliation(s)
- Guoxiang Shen
- Graduate Program in Pharmaceutical Science, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA
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18
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Elloul S, Elstrand MB, Nesland JM, Tropé CG, Kvalheim G, Goldberg I, Reich R, Davidson B. Snail, Slug, and Smad-interacting protein 1 as novel parameters of disease aggressiveness in metastatic ovarian and breast carcinoma. Cancer 2005; 103:1631-43. [PMID: 15742334 DOI: 10.1002/cncr.20946] [Citation(s) in RCA: 325] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
BACKGROUND It was demonstrated previously that the Snail family of transcription factors and Smad-interacting protein 1 (Sip1) regulate E-cadherin and matrix metalloproteinase 2 (MMP-2) expression, cellular morphology, and invasion in carcinoma. For the current study, the authors analyzed the relation between the expression of Snail, Slug, and Sip1; the expression of MMP-2 and E-cadherin; and clinical parameters in patients with metastatic ovarian and breast carcinoma. METHODS One hundred one fresh-frozen, malignant effusions from patients who were diagnosed with gynecologic carcinomas (78 ovarian carcinomas and 23 breast carcinomas) were studied for mRNA expression of Snail, Slug, Sip1, MMP-2, and E-cadherin using reverse transcriptase-polymerase chain reaction analysis. Snail mRNA and E-cadherin protein expression levels also were studied in ovarian carcinoma effusions using in situ hybridization and immunocytochemistry. The results were analyzed for possible correlation with clinicopathologic parameters in both tumor types. RESULTS E-cadherin mRNA expression was lower in breast carcinoma (P = 0.001), whereas Snail expression was higher (P = 0.003). The Snail/E-cadherin ratio (P < 0.001) and the Sip1/E-cadherin ratio (P = 0.002) were higher in breast carcinomas. Sip1 mRNA expression (P < 0.001) and Slug mRNA expression (P < 0.001) were correlated with the expression of MMP-2 in ovarian carcinomas. The Sip1/E-cadherin ratio was higher in primary ovarian carcinomas at the time of diagnosis compared with postchemotherapy ovarian carcinoma effusions (P = 0.003), higher in Stage IV tumors compared with Stage III tumors (P = 0.049), and higher in pleural effusions compared with peritoneal effusions (P = 0.044). In a univariate survival analysis of patients with ovarian carcinoma, a high Sip1/E-cadherin ratio predicted poor overall survival (P = 0.018). High E-cadherin mRNA expression predicted better disease-free survival (P = 0.023), with a similar trend for a low Slug/E-cadherin ratio (P = 0.07). High Snail mRNA expression predicted shorter effusion-free survival (P = 0.008), disease-free survival (P = 0.03), and overall survival (P = 0.008) in patients with breast carcinoma. CONCLUSIONS Transcription factors that regulate E-cadherin were expressed differentially in metastatic ovarian and breast carcinoma. Snail may predict a poor outcome in patients who have breast carcinoma metastatic to effusions. E-cadherin expression generally was conserved in effusions from patients with ovarian carcinoma, but the subset of patients with postulated Sip1-induced repression of this adhesion molecule had a significantly worse outcome. This finding was in agreement with the stronger suppression of E-cadherin by Snail and Sip1 in breast carcinoma effusions, a clinical condition associated with extremely poor survival.
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MESH Headings
- Adenocarcinoma, Clear Cell/genetics
- Adenocarcinoma, Clear Cell/metabolism
- Adenocarcinoma, Clear Cell/secondary
- Adenocarcinoma, Mucinous/genetics
- Adenocarcinoma, Mucinous/metabolism
- Adenocarcinoma, Mucinous/secondary
- Adult
- Aged
- Breast Neoplasms/genetics
- Breast Neoplasms/metabolism
- Breast Neoplasms/pathology
- Cadherins/genetics
- Cadherins/metabolism
- Carcinoma, Ductal/genetics
- Carcinoma, Ductal/metabolism
- Carcinoma, Ductal/secondary
- Carcinoma, Lobular/genetics
- Carcinoma, Lobular/metabolism
- Carcinoma, Lobular/secondary
- Cystadenocarcinoma, Serous/genetics
- Cystadenocarcinoma, Serous/metabolism
- Cystadenocarcinoma, Serous/secondary
- DNA-Binding Proteins/genetics
- DNA-Binding Proteins/metabolism
- Drosophila Proteins/genetics
- Drosophila Proteins/metabolism
- Female
- Gene Expression Regulation, Neoplastic
- Homeodomain Proteins/genetics
- Homeodomain Proteins/metabolism
- Humans
- Immunoenzyme Techniques
- In Situ Hybridization
- Matrix Metalloproteinase 2/genetics
- Matrix Metalloproteinase 2/metabolism
- Middle Aged
- Ovarian Neoplasms/genetics
- Ovarian Neoplasms/metabolism
- Ovarian Neoplasms/pathology
- Prognosis
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- RNA, Neoplasm/genetics
- RNA, Neoplasm/metabolism
- Repressor Proteins/genetics
- Repressor Proteins/metabolism
- Reverse Transcriptase Polymerase Chain Reaction
- Snail Family Transcription Factors
- Survival Rate
- Transcription Factors/genetics
- Transcription Factors/metabolism
- Zinc Finger E-box Binding Homeobox 2
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Affiliation(s)
- Sivan Elloul
- Department of Pharmacology and Experimental Therapeutics, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
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19
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Matsumoto K, Shariat SF, Casella R, Wheeler TM, Slawin KM, Lerner SP. Preoperative Plasma Soluble E-Cadherin Predicts Metastases to Lymph Nodes and Prognosis in Patients Undergoing Radical Cystectomy. J Urol 2003; 170:2248-52. [PMID: 14634390 DOI: 10.1097/01.ju.0000094189.93805.17] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
PURPOSE We have previously reported that high urinary levels of soluble E-cadherin (sE-cadherin) are associated with an increased risk of bladder cancer. We determined whether plasma levels of sE-cadherin are associated with bladder cancer stage and prognosis. MATERIALS AND METHODS The study group consisted of 50 patients who underwent radical cystectomy for muscle invasive cancer or intravesical therapy refractory Tis, Ta, or T1 bladder cancer; and 40 men without cancer. Preoperative plasma levels of sE-cadherin were measured using a commercially available enzyme-linked immunosorbent assay kit. RESULTS Plasma sE-cadherin was higher in patients with bladder cancer than in healthy subjects (p <0.0001) and it was elevated in patients with metastases to regional and distant lymph nodes (p = 0.019 and 0.024, respectively). When adjusted for the effects of clinical stage and grade, preoperative sE-cadherin was independently associated with metastases to regional lymph nodes (p = 0.028) and disease progression (p = 0.006) but not with bladder cancer mortality. In postoperative models preoperative sE-cadherin and lymph node metastases were associated with disease progression (p = 0.017 and 0.042, respectively) after adjusting for the effects of pathological stage, grade and lymphovascular invasion but only lymph node metastases were associated with cancer specific mortality (p = 0.007). CONCLUSIONS Higher plasma sE-cadherin is associated with bladder cancer. Higher preoperative plasma sE-cadherin has the potential to identify patients with metastases to regional and distant lymph nodes who are at increased risk for failure of local therapy with curative intent. These patients may benefit from more extensive lymph node dissection and/or combined modality treatment regimens.
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Affiliation(s)
- Kazumasa Matsumoto
- Scott Department of Urology, Baylor College of Medicine, Houston, Texas 77030, USA
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20
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N/A. N/A. Shijie Huaren Xiaohua Zazhi 2003; 11:1618-1620. [DOI: 10.11569/wcjd.v11.i10.1618] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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21
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Meireles SI, Carvalho AF, Hirata R, Montagnini AL, Martins WK, Runza FB, Stolf BS, Termini L, Neto CEM, Silva RLA, Soares FA, Neves EJ, Reis LFL. Differentially expressed genes in gastric tumors identified by cDNA array. Cancer Lett 2003; 190:199-211. [PMID: 12565175 DOI: 10.1016/s0304-3835(02)00587-6] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Using cDNA fragments from the FAPESP/lICR Cancer Genome Project, we constructed a cDNA array having 4512 elements and determined gene expression in six normal and six tumor gastric tissues. Using t-statistics, we identified 80 cDNAs whose expression in normal and tumor samples differed more than 3.5 sample standard deviations. Using Self-Organizing Map, the expression profile of these cDNAs allowed perfect separation of malignant and non-malignant samples. Using the supervised learning procedure Support Vector Machine, we identified trios of cDNAs that could be used to classify samples as normal or tumor, based on single-array analysis. Finally, we identified genes with altered linear correlation when their expression in normal and tumor samples were compared. Further investigation concerning the function of these genes could contribute to the understanding of gastric carcinogenesis and may prove useful in molecular diagnostics.
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Affiliation(s)
- Sibele I Meireles
- Hospital do Câncer A.C. Camargo, Rua Professor Antonio Prudente 109, 01509-010, São Paulo, SP, Brazil
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22
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Del Buono R, Pignatelli M. The role of the E-cadherin complex in gastrointestinal cell differentiation. Cell Prolif 2003; 32:79-84. [PMID: 10535354 PMCID: PMC6726321 DOI: 10.1046/j.1365-2184.1999.32230079.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Affiliation(s)
- R Del Buono
- Department of Histopathology, Imperial College of Science Technology and Medicine, London, UK
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23
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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.
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Affiliation(s)
- Philip M Carpenter
- Department of Pathology, University of California, Irvine Medical Center, Orange 92868, USA
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24
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Akutagawa N, Nishikawa A, Iwasaki M, Fujimoto T, Teramoto M, Kitajima Y, Endo T, Shibuya M, Kudo R. Expression of vascular endothelial growth factor and E-cadherin in human ovarian cancer: association with ascites fluid accumulation and peritoneal dissemination in mouse ascites model. Jpn J Cancer Res 2002; 93:644-51. [PMID: 12079512 PMCID: PMC5927051 DOI: 10.1111/j.1349-7006.2002.tb01302.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Ascites formation and peritoneal dissemination are critical problems in patients with advanced ovarian cancer. Vascular endothelial growth factor (VEGF), also known as angiogenic growth factor, is a potent mediator of peritoneal fluid accumulation and angiogenesis of tumors. E-Cadherin is an adhesion molecule that is important for cell-to-cell interaction. To elucidate the molecular mechanism of ascites formation and peritoneal dissemination of ovarian cancer, we examined the expression of VEGF and E-cadherin in different ovarian cancer cell lines and utilized nude mice to compare the biological characteristics of ovarian cancer cells. Three human ovarian cancer cell lines (AMOC-2, HNOA and HTBOA) were used in this study. Expression of genes was analyzed by northern blotting and RT-PCR methods. AMOC-2 expressed E-cadherin, but not VEGF. HNOA expressed VEGF without E-cadherin expression. HTBOA expressed both VEGF and E-cadherin. Each human ovarian cancer model revealed a specific feature. The AMOC-2 mouse had a single large peritoneal tumor without ascites or remarkable peritoneal dissemination. HTBOA and HNOA mice had bloody ascites and marked peritoneal dissemination. Introduction of VEGF antisense into HTBOA cells could inhibit the ascites formation. It is suggested that VEGF is important for the ascites formation via the increased vascular permeability effect. The deregulation of E-cadherin expression might be involved in the peritoneal dissemination. These molecules are important for the formation of specific features of advanced ovarian cancer. Ovarian cancer cell lines that had different gene expression patterns produced nude mouse human ovarian cancer models with different characteristics.
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Affiliation(s)
- Noriyuki Akutagawa
- Department of Obstetrics and Gynecology, School of Medicine, Sapporo Medical University, Chuo-ku, Sapporo 060-8543
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25
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Thomas GJ, Speight PM. Cell adhesion molecules and oral cancer. CRITICAL REVIEWS IN ORAL BIOLOGY AND MEDICINE : AN OFFICIAL PUBLICATION OF THE AMERICAN ASSOCIATION OF ORAL BIOLOGISTS 2002; 12:479-98. [PMID: 11806518 DOI: 10.1177/10454411010120060301] [Citation(s) in RCA: 63] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Cell adhesion molecules (CAMs) are found on the surfaces of all cells, where they bind to extracellular matrix molecules or to receptors on other cells. As well as having a structural role, CAMs function as signaling receptors, transducing signals initiated by cellular interactions which regulate many diverse processes, including cell division, migration, and differentiation. Cell adhesion molecules are essential for maintaining stable tissue structure. However, cell adhesion must be dynamic to facilitate the mobility and turnover of cells. In dynamic situations, cells alter their cell-cell and cell-matrix interactions by virtue of altered expression and function of CAMs. The expression of CAMs is normally tightly regulated, thereby controlling cell proliferation, mobility, differentiation, and survival. Many of these processes are misregulated in malignant tumors, and it has been shown that many of the characteristics of tumor cells are attributable to the aberrant expression or function of CAMs. Integrins and E-cadherin are the most important CAMs expressed by stratified squamous epithelium. Altered expression of these molecules has been found in oral carcinoma, where loss of CAM expression is often seen in poorly differentiated lesions. However, up-regulation of certain integrins, such as alphavbeta6, has consistently been found in oral cancer, suggesting that it may play an active role in disease progression.
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Affiliation(s)
- G J Thomas
- Department of Oral Pathology, Eastman Dental Institute for Oral Health Care Sciences, University College London, UK
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26
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Yoshino I, Kase S, Yano T, Sugio K, Sugimachi K. Expression status of E-cadherin and alpha-, beta-, and gamma-catenins in thymoma. Ann Thorac Surg 2002; 73:933-7. [PMID: 11899204 DOI: 10.1016/s0003-4975(01)03434-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND A loss or dysfunction of E-cadherin or catenins, which maintain tissue integrity, is associated with an invasive phenotype of various solid tumors. Therefore, we analyzed the expression of E-cadherin and alpha-catenin, beta-catenin, and gamma-catenin in thymoma tissue specimens to investigate its clinical significance. METHODS The expressions of E-cadherin and alpha-catenin, beta-catenin, and gamma-catenin in thymoma tissues were evaluated in 21 patients, including 9 epithelial predominant type, 5 lymphocytic predominant type, and 7 mixed type patients based on an immunohistochemical analysis using monoclonal antibodies, and the relationship between the expression status and clinicopathologic features was investigated. RESULTS Reduced expressions were observed in 11 patients (52%) for E-cadherin, 10 (45%) for alpha-catenin, 6 (27%) for beta-catenin, and 10 (45%) for gamma-catenin. Such an expression status (reduced or preserved) of the molecules closely correlated with each other. The expression of E-cadherin was well preserved in 5 of 5 patients with lymphocyte predominant type whereas E-cadherin was reduced in 11 of 17 patients with other histologic subtypes. All of the 9 cortex type thymomas (B1 to 3) showed preserved expression of beta-catenin. There was no significant relationship among the expressions of the molecules and the Masaoka stage classification (I versus others). CONCLUSIONS The status of expressions for these molecules may affect the degree of lymphoid infiltration while not affecting the degree of invasiveness in thymoma.
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Affiliation(s)
- Ichiro Yoshino
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
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27
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Mason MD, Davies G, Jiang WG. Cell adhesion molecules and adhesion abnormalities in prostate cancer. Crit Rev Oncol Hematol 2002; 41:11-28. [PMID: 11796229 DOI: 10.1016/s1040-8428(01)00171-8] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Prostate cancer, the leading male cancer in Western countries, has accelerated in its incidence in the past decade. Patients with prostate cancer frequently have a poor prognosis as a result of local or distant spread of cancer. This review summarises some of the recent progress made in understanding the biology of cancer metastasis with a special emphasis on the role of cell adhesion molecules and adhesion abnormalities. The molecular and cellular function of cell adhesion molecules, their role in cancer and cancer progression, the clinical impact of these molecules, and therapeutic considerations are also discussed.
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Affiliation(s)
- Malcolm D Mason
- Department of Clinical Oncology, University of Wales College of Medicine, Health Park, Cardiff, UK.
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28
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Monaghan H, Bubb VJ, Sirimujalin R, Millward-Sadler SJ, Salter DM. Adenomatous polyposis coli (APC), beta-catenin, and cadherin are expressed in human bone and cartilage. Histopathology 2001; 39:611-9. [PMID: 11903580 DOI: 10.1046/j.1365-2559.2001.01287.x] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
AIMS Members of the cadherin and catenin families are involved in chondrogenesis and catenin gene mutations have been detected in malignant tumours of bone. This study was undertaken to assess in detail expression of cadherin, beta-catenin and the associated tumour suppressor gene product APC in bone and cartilage at different stages of human skeletal maturity and in non-neoplastic and neoplastic osteoarticular disease. METHODS AND RESULTS Immunohistochemical staining of formalin-fixed paraffin-embedded normal and osteoarthritic adult articular cartilage, fetal growth plate and a series of tumours of bone and cartilage was undertaken with a panel of antibodies against APC, beta-catenin, and pan-cadherin. This study demonstrated expression of APC, beta-catenin and cadherin in normal and diseased bone and cartilage. APC was present both in osteoblasts and osteoclasts but not in osteocytes. Although only weak APC staining of occasional growth plate hypertrophic chondrocytes and normal articular chondrocytes was seen, APC staining was increased in osteoarthritic articular cartilage. beta-catenin and pan-cadherin staining was strongly positive in osteoclasts and osteoblasts, with expression being lost when bone cells differentiated into osteocytes. Expression of APC, beta-catenin and pan-cadherin in bone tumours was similar to that of non-neoplastic adult tissues. CONCLUSIONS These findings suggest previously unrecognized roles for APC in regulation of function of chondrocytes, osteoblasts and osteoclasts and support the view that catenin-cadherin interactions are important in regulation of bone cell activity. Abnormalities of expression or function of these molecules may be important in formation of bone tumours and their clinical behaviour.
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Affiliation(s)
- H Monaghan
- Department of Pathology, Edinburgh University Medical School, Teviot Place, Edinburgh EH8 9AG, UK.
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29
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El-Bahrawy MA, Poulsom R, Jeffery R, Talbot I, Alison MR. The expression of E-cadherin and catenins in sporadic colorectal carcinoma. Hum Pathol 2001; 32:1216-24. [PMID: 11727261 DOI: 10.1053/hupa.2001.28948] [Citation(s) in RCA: 55] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The E-cadherin/catenin complex plays a major role in epithelial cell-cell adhesion. Immunohistochemical studies have highlighted perturbation in the expression and distribution of E-cadherin and catenins in sporadic colorectal neoplasms. In this study, we compared the expression of E-cadherin and catenins (alpha-, beta-, and gamma-catenin) in 30 sporadic colorectal carcinomas with that in the adjacent nonneoplastic mucosa and assessed whether any perturbation in the level of expression occurred at the messenger RNA (mRNA) or protein level. We also compared the expression of E-cadherin and catenins in 13 lymph node deposits and the primary tumors. Immunohistochemistry was used to study the level of expression and cellular distribution of E-cadherin and catenins. Levels of mRNA were studied by in situ hybridization. E-cadherin and catenin immunoreactivity was increased with cytoplasmic accumulation in more than 85% of the neoplasms. There were marked increases in the levels of mRNA in the carcinomas compared with the nonneoplastic mucosa. Nuclear localization of beta-catenin was higher at the invasive margin of some tumors, but expression of E-cadherin and catenin transcripts in the lymph node deposits showed no consistent relationship to that in the primary tumors.
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Affiliation(s)
- M A El-Bahrawy
- Histopathology Department, Hammersmith Hospital, Imperial College School of Medicine, London, England
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30
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Nawrocki Raby B, Polette M, Gilles C, Clavel C, Strumane K, Matos M, Zahm JM, Van Roy F, Bonnet N, Birembaut P. Quantitative cell dispersion analysis: new test to measure tumor cell aggressiveness. Int J Cancer 2001; 93:644-52. [PMID: 11477573 DOI: 10.1002/ijc.1380] [Citation(s) in RCA: 40] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Tumor progression requires the dispersion of epithelial cells from neoplastic clusters and cell invasion of adjacent stromal connective tissue. Aiming at demonstrating the precise relationships between cell dispersion and cell invasion, related respectively to expression of E-cadherin/catenin complex and matrix metalloproteinases (MMPs), we developed an original in vitro model of cell dispersion analysis. Our study reports the validation of this model that allowed us to analyze and quantify the cell cohesion level by means of time-lapse videomicroscopy and computer analysis based on the observation of spatial and temporal cell distribution. Our model was able to distinguish 2 groups among different human bronchial and mammary epithelial cells previously characterized for the expression of E-cadherin/catenin complex and MMPs and their invasive capacity in the Boyden chamber assay. The first group (16HBE14o(-), MCF-7, T47D) that expressed membranous E-cadherin and beta-catenin, and was negative for MMP-2 expression and non-invasive, displayed a highly cohesive pattern corresponding to a cluster spatial distribution. The second group (Beas2B, BZR, BZR-T33, MDA-MB-231, MDA-MB-435, BT549 and HS578T) that was invasive and showed lack of expression of E-cadherin and a cytoplasmic redistribution of beta-catenin, displayed a dispersed pattern corresponding to a random spatial distribution. Downregulation of E-cadherin by a blocking antibody induced a more random distribution. Conversely, expression of E-cadherin by cDNA transfection induced a cluster distribution. Moreover, tumor cell lines that co-expressed MT1-MMP and MMP-2 (Beas2B, BZR, BZR-T33, MDA-MB-435, BT549 and HS578T) showed a more dispersed pattern than tumor cell lines that did not express MMP-2 (MDA-MB-231). In conclusion, we demonstrated that the spatial group behavior of cell lines, i.e., their cohesion/dispersion ability, reflects their invasive properties. Thus, this model of cell dispersion analysis may represent a new test to measure tumor cell aggressiveness.
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31
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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.
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Affiliation(s)
- Y Ohene-Abuakwa
- Division of Histopathology, Department of Pathology and Microbiology, University of Bristol, Bristol Royal Infirmary, Bristol, UK
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32
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Davidson B, Berner A, Nesland JM, Risberg B, Berner HS, Tropè CG, Kristensen GB, Bryne M, Ann Florenes V. E-cadherin and alpha-, beta-, and gamma-catenin protein expression is up-regulated in ovarian carcinoma cells in serous effusions. J Pathol 2000; 192:460-9. [PMID: 11113863 DOI: 10.1002/1096-9896(2000)9999:9999<::aid-path726>3.0.co;2-m] [Citation(s) in RCA: 83] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
The aims of this study were firstly, to investigate the expression of E-cadherin complex proteins in ovarian carcinoma cells in serous effusions and in primary and metastatic lesions; and secondly to study the value of these four proteins and calretinin, a mesothelial marker, in the differential diagnosis of ovarian carcinoma cells from reactive mesothelial cells in effusions. Sixty-seven malignant effusions and 97 corresponding primary (n=36) and metastatic (n=61) lesions were immunohistochemically stained for E-cadherin and alpha-, beta-, and gamma-catenin. Staining extent and intensity were scored. Effusion specimens were additionally analysed for calretinin immunoreactivity. Membrane immunoreactivity for E-cadherin and alpha-, beta-, and gamma-catenin was detected on carcinoma cells in the majority of the effusions, but rarely on reactive mesothelial cells (p<0.001 for all markers). Calretinin immunoreactivity was confined to mesothelial cells (p<0.001). An association was seen between E-cadherin and alpha-catenin expression, in both effusions and solid tumours, and for beta-catenin in solid tumours (range p<0. 001 to p=0.014). Up-regulation of all four cadherin complex proteins was seen in carcinoma cells in effusions, when compared with corresponding primary tumours (range p<0.001 to p=0.028). As with effusions, metastatic lesions showed up-regulation of alpha-, beta-, and gamma-catenin when compared with primary carcinomas (p=0.002-0. 015). Carcinoma cells in effusions showed in addition elevated levels of E-cadherin when compared with metastatic lesions (p<0.001). Staining results in effusions showed no association with effusion site, tumour type or histological grade. Immunoblotting on 29 malignant effusions confirmed the presence of all four proteins in the majority of samples and co-precipitation of E-cadherin and beta-catenin was seen in ten specimens examined. E-cadherin complex proteins are widely expressed in ovarian carcinoma cells. Together with calretinin, they form a powerful battery of markers for the cytological diagnosis of carcinoma cells in effusions. The up-regulation of E-cadherin complex proteins in serous effusions and metastatic lesions may mark an early metastatic phenotype and possibly mediates survival of tumour cells at these sites through the inhibition of apoptosis.
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Affiliation(s)
- B Davidson
- Department of Pathology, The Norwegian Radium Hospital, Oslo, Norway.
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33
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Kim HC, Wheeler JM, Kim JC, Ilyas M, Beck NE, Kim BS, Park KC, Bodmer WF. The E-cadherin gene (CDH1) variants T340A and L599V in gastric and colorectal cancer patients in Korea. Gut 2000; 47:262-7. [PMID: 10896919 PMCID: PMC1728009 DOI: 10.1136/gut.47.2.262] [Citation(s) in RCA: 47] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
INTRODUCTION Germline mutations in E-cadherin (CDH1) have been reported in families with early onset, diffuse gastric cancer. More recently, mutations in CDH1 have been described in colorectal cancer cell lines. AIMS We have investigated if germline mutations in CDH1 occur among different groups of Korean gastric and colorectal cancer patients, with and without a positive family history. METHODS We studied 131 patients and 168 normal controls (88 Korean and 80 non-Korean). Patients were divided into five groups: group I, 20 gastric cancer patients with a family history; group II, 26 colorectal cancer patients with a family history of gastric cancer (those from familial adenomatous polyposis (FAP) and hereditary non-polyposis colorectal cancer (HNPCC) kindred were excluded); group III, 16 HNPCC patients without identified germline mutations in hMLH1 and hMSH2; group IV, 35 gastric cancer patients without a family history; and group V, 34 colorectal cancer patients without a family history. Polymerase chain reaction, single strand conformational polymorphism analysis, direct sequencing, and genotyping for identified variants were performed. RESULTS Several germline changes in CDH1 were found. In addition to previously described polymorphisms, we found three novel changes, two of which were missense changes (T340A and L599V). T340A was present in one patient in group III and one in group V. L599V was present in one patient in group II, in two in group III, and in one in group IV. T340A was not found in normal controls while L599V was present in two of 88 Korean controls. Patients with these variants may appear to have a tendency to early onset cancer with a positive family history, although differences in frequencies did not reach statistical significance. Genotyping results suggest that these variants might have a common origin, particularly T340A. CONCLUSION We have described two new missense germline variants in CDH1 in various groups of Korean gastrointestinal cancer patients. Further work is required to assess if these variants increase the risk of gastrointestinal cancer.
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Affiliation(s)
- H C Kim
- Cancer and Immunogenetics Laboratory, Imperial Cancer Research Fund, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, UK
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34
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Yu J, Ebert MP, Miehlke S, Rost H, Lendeckel U, Leodolter A, Stolte M, Bayerdörffer E, Malfertheiner P. alpha-catenin expression is decreased in human gastric cancers and in the gastric mucosa of first degree relatives. Gut 2000; 46:639-44. [PMID: 10764706 PMCID: PMC1727909 DOI: 10.1136/gut.46.5.639] [Citation(s) in RCA: 42] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
BACKGROUND AND AIMS The role of altered cell adhesion is critical for the development of epithelial cancers. E-cadherin plays an important role in the maintenance of cell-cell adhesion and its function is thought to be regulated by its associated cytoplasmic proteins, such as alpha-catenin and beta-catenin. To determine the role of alpha-catenin expression in gastric carcinogenesis, we studied its expression in human gastric cancer and in the gastric mucosa of first degree relatives with no clinical disease. METHODS alpha-Catenin expression was assessed by immunohistochemical analysis and reverse transcriptase-polymerase chain reaction (RT-PCR) using gastric tissue specimens from patients with gastric cancer and from the gastric mucosa of first degree relatives of gastric cancer patients and healthy controls. RESULTS mRNA levels of alpha-catenin were reduced or absent in 13 of 19 gastric cancer tissues, which differed significantly from levels found in the tumour free gastric mucosa of cancer patients (p<0.05). Of the cancer samples with altered alpha-catenin mRNA levels, alpha-catenin expression was negative in seven and decreased in six cases. Interestingly, decreased alpha-catenin mRNA expression also occurred in the mucosa of the corpus (11/18) and antrum (4/18) of first degree relatives. In the corpus biopsies alpha-catenin expression was more often decreased or lost compared with the antrum biopsies in first degree relatives and healthy controls (p<0.05). Immunohistochemical analysis revealed membranous expression of alpha-catenin in gastric cancer cells and the non-malignant gastric epithelium. However, some cancers also exhibited loss of membranous staining. Generally, loss or downregulation of alpha-catenin mRNA in the gastric mucosa was associated with Helicobacter pylori infection (p<0.05). CONCLUSION Our findings suggest that loss or downregulation of alpha-catenin expression may be an early event in gastric carcinogenesis and may be associated with H pylori infection.
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Affiliation(s)
- J Yu
- Department of Gastroenterology, Hepatology, and Infectious Diseases, Otto-von-Guericke University, D-39120 Magdeburg, Germany
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35
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Ramesh S, Nash J, McCulloch PG. Reduction in membranous expression of beta-catenin and increased cytoplasmic E-cadherin expression predict poor survival in gastric cancer. Br J Cancer 1999; 81:1392-7. [PMID: 10604738 PMCID: PMC2362972 DOI: 10.1038/sj.bjc.6693437] [Citation(s) in RCA: 62] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
beta-catenin, a component of the E-cadherin-catenin cell adhesion complex, also plays a separate intracellular signalling role, interacting with APC protein. Intracellular accumulation of beta-catenin is common in colorectal neoplasia. beta-catenin abnormalities are associated with poor survival in gastric cancer, but previous studies do not differentiate between membrane-associated and intracellular beta-catenin. In this study we aimed to determine which type of expression abnormalities for E-cadherin, beta-catenin and alpha-catenin correlate with clinico-pathological features and survival in gastric cancer. Immunoperoxidase staining of paraffin-embedded sections from 40 gastric cancers was performed for E-cadherin, alpha- and beta-catenins using microwave unmasking and an avidin-biotin technique. Clinical data were obtained from case records and cancer registry records. Reduced membranous expression of beta-catenin occurred in 10/12 (83%) diffuse and 8/28 (29%) intestinal tumours (P= 0.0014), and was associated with poor differentiation (P= 0.0015) and short survival (P= 0.032), but not with age, sex, tumour size or nodal status. Nuclear expression of beta-catenin was uncommon; cytoplasmic expression was observed in 13/40 cases (33%) but did not correlate with histology, tumour grade or survival. Reduced E-cadherin membrane expression was associated with lymph node metastasis (P= 0.02). Neither E-cadherin or alpha-catenin expression correlated with survival. Reduced membranous expression of beta-catenin predicts poor prognosis in gastric cancer, whilst ectopic intracellular expression is relatively rare. The apparent differences in beta-catenin expression from those found in colon cancer merit further study.
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Affiliation(s)
- S Ramesh
- Department of Surgery, University of Liverpool, UK
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36
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Mertens C, Kuhn C, Moll R, Schwetlick I, Franke WW. Desmosomal plakophilin 2 as a differentiation marker in normal and malignant tissues. Differentiation 1999; 64:277-90. [PMID: 10374264 DOI: 10.1046/j.1432-0436.1999.6450277.x] [Citation(s) in RCA: 70] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Plakophilin 2 (PKP2) is a widespread protein which shows a remarkable dual location: On the one hand, it appears as a constitutive karyoplasmic protein and on the other it is a desmosomal plaque component of most, probably all, desmosome-possessing tissues and cell culture lines. Here we report on its desmosomal occurrence as revealed by immunocytochemical results obtained with three PKP2-specific murine monoclonal antibodies (mAbs) PP2-62, PP2-86 and PP2-150. These mAbs detect PKP2 in characteristic desmosomes of most normal cells, including simple and stratified epithelia as well as non-epithelial tissues such as myocardium and lymph node follicles. In addition, however, several normal tissues consistently display a differentiation-related PKP2 distribution, for example an absence of immunostaining in the "keratinizing" local specializations of the thymic epithelial reticulum, i.e. Hassall's corpuscles, and the restriction of PKP2 to the stratum basale of most stratified squamous epithelia, in contrast to its absence in upper strata, which contain PKP1- or PKP3-rich desmosomes instead. Taking advantage of the reactivity of mAb PP2-150 with formalin-fixed, paraffin-embedded material, a series of human carcinomas (n = 37) has also been analyzed. The results suggest that mAbs to PKP2 may serve as markers for the identification and characterization of carcinomas derived from--or corresponding to--simple or complex epithelia. Thus consistent PKP2 immunostaining has been observed in all 18 cases of adenocarcinomas tested, but more variable and heterogeneous staining has been noted in squamous cell carcinomas, depending on the specific tumor type. The potential value of such mAbs for cell typing in normal and embryonic tissues and for detecting cell subpopulations with different degrees of differentiation is discussed with respect to their possible application in tumor diagnosis.
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Affiliation(s)
- C Mertens
- Division of Cell Biology, German Cancer Research Center, Heidelberg, Germany
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37
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Abstract
AIMS Reduction or loss of E-cadherin expression was examined in early gastric carcinomas and precursor lesions with the following aims: (1) to assess overall E-cadherin expression in various stages of gastric carcinogenesis; (2) to correlate E-cadherin expression with the Lauren type, the grade of differentiation and the type of growth pattern of the tumours; and (3) to correlate E-cadherin expression with lymph node metastasis and overall prognosis. METHODS AND RESULTS Forty-five paraffin-embedded gastrectomy specimens from early carcinomas were examined for the presence of various precursor lesions. The Lauren type, the grade of differentiation and the type of growth pattern were reassessed for all early carcinomas. E-cadherin expression was examined using antibody HECD-1. Whereas E-cadherin was strongly and evenly expressed in the gastric foveolar epithelium, intestinal metaplasia and early gastric carcinomas showed a lower expression. A significant difference in E-cadherin expression was found between the Lauren types (P < 0.0001). Moreover, an inverse correlation was found between E-cadherin expression and histological grade (P < 0.0001). Neither a difference in E-cadherin expression between the various growth types nor an association with lymph node metastasis and overall prognosis was found. CONCLUSIONS The Lauren types differ in E-cadherin expression, although reduced E-cadherin expression in all probability rather reflects poor differentiation than a diffuse growth pattern 'genotype'. Moreover, E-cadherin expression does not underlie the difference in biological behaviour of early carcinomas with different types of growth pattern. Finally, E-cadherin expression is not associated with lymph node status and 5-year survival rate, at least not in early gastric carcinomas.
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Affiliation(s)
- P Blok
- Department of Pathology, Westeinde Ziekenhuis, The Netherlands
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38
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Jawhari AU, Noda M, Farthing MJ, Pignatelli M. Abnormal expression and function of the E-cadherin-catenin complex in gastric carcinoma cell lines. Br J Cancer 1999; 80:322-30. [PMID: 10408833 PMCID: PMC2362351 DOI: 10.1038/sj.bjc.6690358] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
Dysfunction of the cadherin-catenin complex, a key component of adherens junctions, is thought to confer invasive potential to cells. The aim of this study is to examine the expression and function of the E-cadherin/catenin complex in gastric carcinoma cell lines. Expression of E-cadherin, alpha, beta and gamma-catenin and p120ctn, and of the adenomatous polyposis coli protein (APC), together with function of the cadherin-catenin complex was examined in a panel of gastric carcinoma cell lines, using immunocytochemistry, Western blotting and a cell-cell aggregation assay. Protein interactions were examined by sequential immunoprecipitation and immunoblotting with antibodies to E-cadherin, alpha, beta and gamma-catenin, p120ctn and APC. Abnormalities of E-cadherin, alpha- and beta-catenin expression, were associated with disturbance of E-cadherin-catenin complex composition, loss of membranous localization and loss of calcium-dependent aggregation in six gastric carcinoma cell lines. APC protein expression and interaction with beta-catenin was preserved in five cell lines. We demonstrate frequent abnormalities of expression and function of E-cadherin and catenins, and associated disturbance of E-cadherin-mediated intercellular adhesion in gastric carcinoma cell lines. These findings support the tumour suppressor role of the E-cadherin and its contribution to the development and progression of the neoplastic phenotype in gastric carcinoma.
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Affiliation(s)
- A U Jawhari
- Digestive Diseases Research Centre, St Bartholomew's and the Royal London School of Medicine and Dentistry, Whitechapel, London, UK
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Paria BC, Zhao X, Das SK, Dey SK, Yoshinaga K. Zonula occludens-1 and E-cadherin are coordinately expressed in the mouse uterus with the initiation of implantation and decidualization. Dev Biol 1999; 208:488-501. [PMID: 10191061 DOI: 10.1006/dbio.1999.9206] [Citation(s) in RCA: 114] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Two-way interactions between the blastocyst trophectoderm and the uterine luminal epithelium are essential for implantation. The key events of this process are cell-cell contact of trophectoderm cells with uterine luminal epithelial cells, controlled invasion of trophoblast cells through the luminal epithelium and the basement membrane, transformation of uterine stromal cells surrounding the blastocyst into decidual cells, and protection of the "semiallogenic" embryo from the mother's immunological responses. Because cell-cell contact between the trophectoderm epithelium and the luminal epithelium is essential for implantation, we investigated the expression of zonula occludens-1 (ZO-1) and E-cadherin, two molecules associated with epithelial cell junctions, in the mouse uterus during the periimplantation period. Preimplantation uterine epithelial cells express both ZO-1 and E-cadherin. With the initiation and progression of implantation, ZO-1 and E-cadherin are expressed in stromal cells of the primary decidual zone (PDZ). As trophoblast invasion progresses, these two molecules are expressed in stroma in advance of the invading trophoblast cells. These results suggest that expression of these adherence and tight junctions molecules in the PDZ serves to function as a permeability barrier to regulate access of immunologically competent maternal cells and/or molecules to the embryo and provide homotypic guidance of trophoblast cells in the endometrium.
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Affiliation(s)
- B C Paria
- Department of Molecular and Integrative Physiology, Ralph L. Smith Research Center, University of Kansas Medical Center, Kansas City, Kansas, 66160-7338, USA
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40
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Protheroe AS, Banks RE, Mzimba M, Porter WH, Southgate J, Singh PN, Bosomworth M, Harnden P, Smith PH, Whelan P, Selby PJ. Urinary concentrations of the soluble adhesion molecule E-cadherin and total protein in patients with bladder cancer. Br J Cancer 1999; 80:273-8. [PMID: 10390008 PMCID: PMC2363021 DOI: 10.1038/sj.bjc.6690351] [Citation(s) in RCA: 24] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Reduced expression of the adhesion molecule E-cadherin has been associated with increased invasiveness and poorer survival in patients with bladder cancer. We have examined soluble E-cadherin (sE-cadherin) and total protein concentrations in urine from patients with bladder cancer (n = 34), non-neoplastic benign urological diseases (n = 14) and healthy controls (n = 21) to determine their diagnostic and prognostic significance. Soluble E-cadherin concentrations of the cancer group were significantly higher (P < 0.001) than those of the controls but the benign group was not significantly different from either the cancer group or the controls. When sE-cadherin concentrations were adjusted for creatinine, similar but more statistically significant results were obtained and the benign group was significantly elevated compared with the controls (P < 0.01). No differences were apparent between the invasive (pT1-4) and non-invasive (pTa) cancers. Urinary total protein concentrations in the cancer group were significantly higher than the controls (P < 0.001) and the benign group (P < 0.05) although no difference was seen between the benign group and patients with non-invasive (pTa) cancer or between the benign group and controls. When expressed as the protein/creatinine index, results were similar but more statistically significant and a significant difference was seen between invasive and non-invasive cancers (P < 0.01). Only the protein/creatinine index correlated significantly with stage of the tumour (P < 0.01). It is concluded that urinary sE-cadherin measurements are of no greater value than urinary total protein.
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Affiliation(s)
- A S Protheroe
- Imperial Cancer Research Fund Cancer Medicine Research Unit, St James's University Hospital, Leeds, UK
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El-Bahrawy MA, Pignatelli M. E-cadherin and catenins: molecules with versatile roles in normal and neoplastic epithelial cell biology. Microsc Res Tech 1998; 43:224-32. [PMID: 9840800 DOI: 10.1002/(sici)1097-0029(19981101)43:3<224::aid-jemt4>3.0.co;2-q] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
E-cadherin and its associated cytoplasmic proteins alpha-, beta-, and gamma-catenin, play a crucial role in epithelial cell-cell adhesion and in the maintenance of tissue architecture. Perturbation in the expression or function of any of these molecules results in loss of intercellular adhesion, with possible consequent cell transformation and tumour progression. The catenins are connected to many structural and functional proteins, which in turn influence their functions. Among these molecules are type 1 growth factor receptors, which along with other molecules are believed to alter the function of catenins through tyrosine phosphorylation. A recent finding is the association between the catenins and the adenomatous polyposis coli gene product (APC). APC mutation is an early event in colorectal carcinogenesis. It may possibly do so through perturbation of the critical cadherin/catenin complex. Further studies of the cadherin/catenin complex and its connections may give insight into the early molecular interactions critical to the initiation and progression oftumours, which should aid in the development of novel therapeutic strategies for both prevention and treatment.
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Affiliation(s)
- M A El-Bahrawy
- Division of Investigative Science, Imperial College of Science, Technology and Medicine, Hammersmith Campus, London, UK
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42
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Nawrocki B, Polette M, Van Hengel J, Tournier JM, Van Roy F, Birembault P. Cytoplasmic redistribution of E-cadherin-catenin adhesion complex is associated with down-regulated tyrosine phosphorylation of E-cadherin in human bronchopulmonary carcinomas. THE AMERICAN JOURNAL OF PATHOLOGY 1998; 153:1521-30. [PMID: 9811344 PMCID: PMC1853397 DOI: 10.1016/s0002-9440(10)65740-9] [Citation(s) in RCA: 56] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The E-cadherin-catenin complex, by mediating intercellular adhesion, regulates the architectural integrity of epithelia. Down-regulation of its expression is thought to contribute to invasion of carcinoma cells. To investigate the involvement of the E-cadherin-catenin adhesion system in the progression of human bronchopulmonary carcinomas, we compared the immunohistochemical distribution of E-cadherin, alpha-catenin, and beta-catenin in four human bronchial cancer cell lines with different invasive abilities and in 44 primary bronchopulmonary tumors. Although invasive bronchial cell lines did not express E-cadherin and alpha-catenin, complete down-regulation of cadherin-catenin complex expression was a rare event in vivo in bronchopulmonary carcinomas. Nevertheless, a spotty and cytoplasmic pattern of E-cadherin and catenins was observed in 32 primary tumors, only in invasive tumor clusters. Immunoprecipitation experiments showed that this redistribution was not related to a disruption of cadherin-catenin interaction but to down-regulated tyrosine phosphorylation of E-cadherin. We conclude that loss of E-cadherin and/or catenins is not a prominent early event in the invasive progression of human bronchopulmonary carcinomas in vivo. The decreased tyrosine phosphorylation of E-cadherin may reflect a loss of functionality of the complex and implicates a major role in tumor invasion.
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Affiliation(s)
- B Nawrocki
- INSERM U.314, IFR 53, Unité de Biologie Cellulaire, Laboratoire Pol Bouin, CHU, Reims, France.
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De Leeuw WJ, Berx G, Vos CB, Peterse JL, Van de Vijver MJ, Litvinov S, Van Roy F, Cornelisse CJ, Cleton-Jansen AM. Simultaneous loss of E-cadherin and catenins in invasive lobular breast cancer and lobular carcinoma in situ. J Pathol 1997; 183:404-11. [PMID: 9496256 DOI: 10.1002/(sici)1096-9896(199712)183:4<404::aid-path1148>3.0.co;2-9] [Citation(s) in RCA: 229] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Loss of expression of the intercellular adhesion molecule E-cadherin frequently occurs in invasive lobular breast carcinomas as a result of mutational inactivation. Expression patterns of E-cadherin and the molecules comprising the cytoplasmic complex of adherens junctions, alpha-, beta- and gamma-catenin, were studied in a series of 38 lobular breast carcinomas with known E-cadherin mutation status. The effect of loss of E-cadherin by mutational inactivation (or other mechanisms) on the expression of catenins was investigated. Complete loss of plasma membrane-associated E-cadherin expression was observed in 32 out of 38 invasive lobular carcinomas, for which in 21 cases a mutation was found in the extracellular domain of E-cadherin. In total, 15 frameshift mutations of small deletions or insertions, ranging from 1 to 41 bp, three non-sense mutations, and three splice mutations were identified. Mutations were scattered over the whole coding region and no hot spots could be detected. In all cases, simultaneous loss of E-cadherin and alpha- and beta-catenin expression was found; in 50 per cent of these cases, additional loss of gamma-catenin was observed. In six invasive lobular carcinomas, expression of both E-cadherin and catenins was retained. In none of these carcinomas was an E-cadherin mutation detected. Lobular carcinoma in situ adjacent to invasive lobular carcinoma showed simultaneous loss of E-cadherin and catenins in all the cases studied--remarkably, also, in four cases positive for E-cadherin and catenin expression in the invasive component. These results indicate that simultaneous loss of E-cadherin and alpha-, beta- and gamma-catenin may be an important step in the formation of lobular carcinoma in situ, as a precursor of invasive lobular breast cancer. Events additional to E-cadherin inactivation must be involved in the transition of lobular carcinoma in situ to invasive lobular carcinoma.
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Affiliation(s)
- W J De Leeuw
- Department of Pathology, Leiden University Medical Center, The Netherlands
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44
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Nishi N, Inui M, Kishi Y, Miyanaka H, Wada F. Isolation and characterization of invasive and noninvasive variants of a rat bladder tumor cell line. Jpn J Cancer Res 1997; 88:831-8. [PMID: 9369930 PMCID: PMC5921519 DOI: 10.1111/j.1349-7006.1997.tb00458.x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
We isolated, in vitro, spontaneous variants of the rat bladder tumor NBT-II cell line with a distinctive morphology. Of five sublines obtained, three (NBT-L1, L2a and L2b) exhibited an elongated shape and moderate to high invasive activity in vitro. The other two sublines (NBT-T1 and T2) formed tight colonies and exhibited very low or negligible invasive activity. The contents of mRNAs coding for E-cadherin and cadherin-associated molecules (alpha-catenin and beta-catenin) were not correlated with the invasive activity of the cells. However, the expression level of the E-cadherin protein, but not those of catenins, was lower in invasive cells (NBT-L1, L2a and L2b) than in noninvasive cells (NBT-T1 and T2). Analysis of mRNAs coding for several growth factors and their receptors showed that the transforming growth factor alpha mRNA content in invasive cells was higher than that in noninvasive cells, and that the content of epidermal growth factor receptor mRNA was low in NBT-T2. Although NBT-II is known to acquire a fibroblastic appearance and cell motility in response to several growth factors, the conditioned media of the invasive sublines hardly affected the morphology or motility of noninvasive cells. These results indicate that the decreased E-cadherin expression is closely associated with the transition from the noninvasive to the invasive phenotype of the bladder tumor cells, and that a post-transcriptional process is important in the control of E-cadherin expression in the cells. These sublines may be useful as models for studies on the progression of bladder tumors.
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Affiliation(s)
- N Nishi
- Department of Endocrinology, Faculty of Medicine, Kagawa Medical University
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45
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Monier-Gavelle F, Duband JL. Cross talk between adhesion molecules: control of N-cadherin activity by intracellular signals elicited by beta1 and beta3 integrins in migrating neural crest cells. J Cell Biol 1997; 137:1663-81. [PMID: 9199179 PMCID: PMC2137812 DOI: 10.1083/jcb.137.7.1663] [Citation(s) in RCA: 126] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
During embryonic development, cell migration and cell differentiation are associated with dynamic modulations both in time and space of the repertoire and function of adhesion receptors, but the nature of the mechanisms responsible for their coordinated occurrence remains to be elucidated. Thus, migrating neural crest cells adhere to fibronectin in an integrin-dependent manner while maintaining reduced N-cadherin-mediated intercellular contacts. In the present study we provide evidence that, in these cells, the control of N-cadherin may rely directly on the activity of integrins involved in the process of cell motion. Prevention of neural crest cell migration using RGD peptides or antibodies to fibronectin and to beta1 and beta3 integrins caused rapid N-cadherin-mediated cell clustering. Restoration of stable intercellular contacts resulted essentially from the recruitment of an intracellular pool of N-cadherin molecules that accumulated into adherens junctions in tight association with the cytoskeleton and not from the redistribution of a preexisting pool of surface N-cadherin molecules. In addition, agents that cause elevation of intracellular Ca2+ after entry across the plasma membrane were potent inhibitors of cell aggregation and reduced the N-cadherin- mediated junctions in the cells. Finally, elevated serine/ threonine phosphorylation of catenins associated with N-cadherin accompanied the restoration of intercellular contacts. These results indicate that, in migrating neural crest cells, beta1 and beta3 integrins are at the origin of a cascade of signaling events that involve transmembrane Ca2+ fluxes, followed by activation of phosphatases and kinases, and that ultimately control the surface distribution and activity of N-cadherin. Such a direct coupling between adhesion receptors by means of intracellular signals may be significant for the coordinated interplay between cell-cell and cell-substratum adhesion that occurs during embryonic development, in wound healing, and during tumor invasion and metastasis.
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Affiliation(s)
- F Monier-Gavelle
- Institut Jacques Monod, Centre National de la Recherche Scientifique (CNRS) et Université Paris 7-Denis Diderot, CNRS et Université Pierre et Marie Curie, 75252 Paris, France
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46
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Han AC, Peralta-Soler A, Knudsen KA, Wheelock MJ, Johnson KR, Salazar H. Differential expression of N-cadherin in pleural mesotheliomas and E-cadherin in lung adenocarcinomas in formalin-fixed, paraffin-embedded tissues. Hum Pathol 1997; 28:641-5. [PMID: 9190996 DOI: 10.1016/s0046-8177(97)90171-4] [Citation(s) in RCA: 68] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
The differential diagnosis of pleural mesotheliomas and lung adenocarcinomas presents a continued challenge in the practice of surgical pathology. Paraffin immunohistochemistry (IHC) using different panels of antibodies can be helpful in some cases, but, as yet, no antigen is expressed specifically in mesotheliomas nor in adenocarcinomas. Using well characterized monoclonal antibodies (MAb) that recognized distinct mesenchymal and epithelial adhesion proteins, N-cadherin (13A9 MAb) and E-cadherin (E9 MAb), respectively, we found previously that in frozen-section IHC mesotheliomas and adenocarcinomas had distinct cadherin phenotypes: mesotheliomas were positive for N-cadherin, and lung adenocarcinomas were positive for E-cadherin. Using antigen-retrieval methods, we successfully extended our study to formalin-fixed, paraffin-embedded tissue sections. Tumors from 28 patients (14 originally diagnosed as mesotheliomas, and 14 diagnosed as adenocarcinomas) were stained with 13A9 MAb and E9 MAb. Review of hematoxylin-eosin sections excluded from analysis one case previously diagnosed as mesothelioma, which represented a hemangiopericytoma. Of the remaining 27 cases, 12 of 13 mesotheliomas were positive for N-cadherin and negative for E-cadherin. The exception was a multifocal microscopic papillary tumor of apparent mesothelial origin, which was negative for both N-cadherin and E-cadherin. Conversely, 13 of 14 adenocarcinomas were E-cadherin positive and N-cadherin negative except for one adenocarcinoma with focal N-cadherin expression. One case of a poorly differentiated adenocarcinoma invading skeletal muscle was negative for both 13A9 and E9. These studies confirmed the utility of the cadherin antibodies in distinguishing pleural mesotheliomas from lung adenocarcinomas. The reactivity of the cadherin-specific antibodies with antigens in paraffin sections make them powerful and reliable markers in the practice of diagnostic surgical pathology.
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Affiliation(s)
- A C Han
- Department of Pathology, the Reading Hospital and Medical Center, West Reading, PA 19612, USA
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47
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Jankowski JA, Bedford FK, Kim YS. Changes in gene structure and regulation of E-cadherin during epithelial development, differentiation, and disease. PROGRESS IN NUCLEIC ACID RESEARCH AND MOLECULAR BIOLOGY 1997; 57:187-215. [PMID: 9175434 DOI: 10.1016/s0079-6603(08)60281-0] [Citation(s) in RCA: 22] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Affiliation(s)
- J A Jankowski
- Department of Medicine, University of Birmingham, England
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48
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Gabbert HE, Mueller W, Schneiders A, Meier S, Moll R, Birchmeier W, Hommel G. Prognostic value of E-cadherin expression in 413 gastric carcinomas. Int J Cancer 1996; 69:184-9. [PMID: 8682585 DOI: 10.1002/(sici)1097-0215(19960621)69:3<184::aid-ijc6>3.0.co;2-w] [Citation(s) in RCA: 96] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
E-cadherin is a Ca(2+)-dependent intercellular adhesion molecule known to exert an invasion-suppressor function. In the present study, E-cadherin expression was immunohistochemically investigated in a retrospective series of 413 RO-resected gastric carcinomas using the monoclonal antibody (MAb) 5H9. Of these cases, 108 tumors revealed a preserved E-cadherin expression similar to that of normal gastric mucosa. In 95 tumors, E-cadherin expression was moderately reduced and in 86 tumors highly reduced. In 124 tumors, no or only a very weak dotted expression could be detected. There was a significant correlation between the degree of E-cadherin expression and the grade of tumor differentiation, as well as with histological type according to the Laurén and the WHO classifications. In contrast, no correlation could be demonstrated between E-cadherin expression and the prognostic parameters depth of invasion, lymph node involvement and vascular invasion. As shown by univariate Cox regression analysis, patients with E-cadherin-positive tumors had significantly better 3-and 5-year survival rates than patients with E-cadherin-negative tumors. This prognostic impact remained present in a multivariate Cox regression analysis, including the prognostic parameters pT category, pN category and vascular invasion.
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Affiliation(s)
- H E Gabbert
- Institute of Pathology, University of Düsseldorf, Germany
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49
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Ross JS, Cheung C, Sheehan C, del Rosario AD, Bui HX, Fisher HA. E-cadherin cell-adhesion molecule expression as a diagnostic adjunct in urothelial cytology. Diagn Cytopathol 1996; 14:310-5. [PMID: 8725130 DOI: 10.1002/(sici)1097-0339(199605)14:4<310::aid-dc6>3.0.co;2-j] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
E-cadherin (E-CD) is a cell-adhesion molecule that has been associated with invasion and metastasis in a wide variety of human neoplasms. We have recently shown that, although decreased E-CD expression is associated with increased bladder-wall invasion and higher tumor grade of infiltrating transitional cell carcinomas (TCC), E-CD expression in the exophytic portion of pure papillary and papillary-infiltrating TCC is increased over that of normal transitional cells. To evaluate whether E-CD levels could serve as a diagnostic adjunct in urinary cytology specimens, we stained 40 alcohol-fixed bladder-washing cytospin preparations with an avidin-biotin-peroxidase method using a monoclonal antibody to E-CD (Sigma Chemical Co., St. Louis, MO). E-CD expression level was defined as a high-intensity or low-intensity staining increase over background squamous cell staining for the transitional cells in 21 biopsy-proven transitional cell carcinomas with papillary components, and in 19 benign or reactive control specimens. Twenty-one of 21 TCC (100%) showed an increased E-CD level over background, with 13 low-intensity and 8 highintensity cases. Ten of 19 benign cases (53%) showed increased E-CD staining over background, with 8 low-intensity and 2 highintensity cases. This difference between malignant and benign specimens was statistically significant (chi-square test. P approximately 0.001). We conclude that increased E-CD expression in the papillary components of TCC can be identified in urinary cytology specimens, may reflect the physical and chemical structural makeup of papillary architecture, and warrants further study as a diagnostic adjunct in the interpretation of urine cytology specimens.
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Affiliation(s)
- J S Ross
- Department of Pathology, Albany Medical Center, NY 12208, USA
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50
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Wakatsuki S, Watanabe R, Saito K, Saito T, Katagiri A, Sato S, Tomita Y. Loss of human E-cadherin (ECD) correlated with invasiveness of transitional cell cancer in the renal pelvis, ureter and urinary bladder. Cancer Lett 1996; 103:11-7. [PMID: 8616803 DOI: 10.1016/0304-3835(96)04194-8] [Citation(s) in RCA: 38] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Loss or decreased expression of E-cadherin (ECD), which forms an epithelial junction complex that includes several other proteins and triggers signal transduction, may contribute to tumor progression. In the present study, we examined 90 transitional cell cancers (TCCs), 47 urinary bladder cancers and 43 ureteral or renal pelvic cancers, as well as TCC and papilloma cell lines to determine whether they express ECD. We classified ECD expression into normo-expression (like normal epithelial), decreased and loss of ECD staining on TCCs (urinary bladder, renal pelvic or ureteral). We found that low-stage TCCs expressed normal ECD in 68%, decreased of ECD in 20% and loss of ECD in 12%, whereas high-stage TCCs expressed 29%, 41% and 30% of ECD staining, respectively (P < 0.01). Furthermore, grade 1 TCCs were all estimated to show normo-expression, grade 2 TCCS expressed normal ECD in 49%, decreased of ECD in 41% and loss of ECD in 10% grade 3 TCCs classified as 20%, 30% and 50%, respectively (P < 0.01). Staining for cultured cell lines showed positive membranous staining for ECD in a benign papilloma cell line, RT4 and a TCC cell line, HT1376, but not in a TCC cell line, T24. Reverse-transcription polymerase chain reaction showed the presence of ECD and alpha-catenin mRNA in RT4 and HT1376, and only alpha-catenin in T24. Thus, it is more likely that decrease or loss of ECD might contribute to the malignant character of tumor cells and result in tumor progression.
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Affiliation(s)
- S Wakatsuki
- Department of Urology, Niigata University School of Medicine, Japan
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