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Chang K, Jiang L, Sun Y, Li H. Effect of E-cadherin on Prognosis of Colorectal Cancer: A Meta-Analysis Update. Mol Diagn Ther 2022; 26:397-409. [PMID: 35732878 DOI: 10.1007/s40291-022-00593-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/25/2022] [Indexed: 12/15/2022]
Abstract
PURPOSE The effect of E-cadherin on colorectal cancer is still controversial. In order to clarify the effect of E-cadherin on the prognosis and clinicopathological features of colorectal cancer, a meta-analysis was conducted. METHODS PubMed, Embase and Cochrane Library were used to collect all relevant literature published before November 2021, and the corresponding data was extracted to analyze the correlation between the expression of E-cadherin and the prognosis and clinicopathological features of colorectal cancer. In addition, the Gene Expression Profiling Interactive Analysis (GEPIA) was used to validate our results. RESULTS Fifty-two studies, including 9591 patients, were included in this meta-analysis. According to the meta-analysis, low expression of E-cadherin was significantly associated with shorter overall survival (OS) (hazard ratio [HR] 2.09, 95% confidence interval [CI]1.67-2.62; Z = 6.42, p = 0.000) and disease-free survival (DFS) (HR 2.03, 95% CI 1.71-2.42; Z = 7.95, p = 0.000). In addition, low expression of E-cadherin resulted in higher risk of low differentiation (odds ratio [OR] 0.35, 95% CI 0.25-0.50; p = 0.000), high risk of distant metastasis (OR 0.45, 95% CI 0.35-0.58; p = 0.000), high risk of vascular invasion (OR 0.61, 95% CI 0.45-0.83; p = 0.002), higher risk of lymph node metastasis (OR 0.54, 95% CI 0.42-0.69; p = 0.000), high risk of lymphatic invasion (OR 0.56, 95% CI 0.40-0.80; p = 0.001), high risk of deep infiltration (OR 0.63, 95% CI 0.50-0.80; p = 0.000), later TNM stage (OR 0.60, 95% CI 0.46-0.78; p = 0.000) and late Dukes' stage (OR 0.35,95% CI 0.25-0.49; p = 0.000), but wasn't associated with tumor size (OR 0.90, 95% CI 0.71-1.15; p = 0.406).The results of GEPIA showed that E-cadherin mRNA expression in colorectal cancer tumor tissues and normal tissues had no difference, and had no effect on OS and DFS. CONCLUSION Although not supported by GEPIA, our meta-analysis provided abundant data to suggest that low expression of E-cadherin is associated with poor prognosis in colorectal cancer patients and is an important factor influencing adverse clinicopathological features. Therefore, E-cadherin may be used to predict the prognosis of colorectal cancer and provide guidance for clinical treatment.
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Affiliation(s)
- Kaibin Chang
- Department of Stomach and Intestine, Yantai Affiliated Hospital of Binzhou Medical University, 717 Jinbu Street, Yantai, 264100, Shandong Province, China
| | - Lei Jiang
- Department of Stomach and Intestine, Yantai Affiliated Hospital of Binzhou Medical University, 717 Jinbu Street, Yantai, 264100, Shandong Province, China
| | - Yifeng Sun
- Department of Stomach and Intestine, Yantai Affiliated Hospital of Binzhou Medical University, 717 Jinbu Street, Yantai, 264100, Shandong Province, China
| | - He Li
- Department of Stomach and Intestine, Yantai Affiliated Hospital of Binzhou Medical University, 717 Jinbu Street, Yantai, 264100, Shandong Province, China.
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Losi L, Zanocco-Marani T, Grande A. Cadherins down-regulation: towards a better understanding of their relevance in colorectal cancer. Histol Histopathol 2020; 35:1391-1402. [PMID: 32567668 DOI: 10.14670/hh-18-236] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
The down-regulation of cadherin expression in colorectal cancer (CRC) has been widely studied. However, existing data on cadherin expression are highly variable and its relevance to CRC development has not been completely established. This review examines published studies on cadherins whose down-regulation has been already demonstrated in CRC, trying to establish a relationship with promoter methylation, the capacity to influence the Wnt / CTNNB1 (catenin beta 1, beta-catenin) signalling pathway and the clinical implications for disease outcome. Moreover, it also analyses factors that may explain data variability and highlights the importance of considering the altered subcellular localization of the examined cadherins. The results of this survey reveal that thirty of one hundred existing cadherins appear to be down-regulated in CRC. Among these, ten are cadherins, sixteen are protocadherins, equally divided between clustered and non clustered, and four are cadherin - related. These findings suggest that, to better define the role played by cadherin down-regulation in CRC pathogenesis, the expression of multiple rather than individual cadherins should be taken into account and further functional studies are necessary to clarify the relative ability of individual cadherins to inhibit CTNNB1 therefore acting as tumor suppressors.
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Affiliation(s)
- Lorena Losi
- Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
| | | | - Alexis Grande
- Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy
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Jurčić P, Radulović P, Balja MP, Milošević M, Krušlin B. E-cadherin and NEDD9 expression in primary colorectal cancer, metastatic lymph nodes and liver metastases. Oncol Lett 2019; 17:2881-2889. [PMID: 30854064 PMCID: PMC6365943 DOI: 10.3892/ol.2019.9917] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2017] [Accepted: 12/21/2018] [Indexed: 12/13/2022] Open
Abstract
In Croatia, colorectal cancer mortality rates in males are the third highest in Europe, after Hungary and Slovakia. The results for females rank Croatia in second place after Hungary. According to previous studies, the loss of E-cadherin expression and the higher expression of neural precursor cell-expressed developmentally downregulated 9 (NEDD9) are associated with a worse prognosis. The aim of the present study was to analyze the immunohistochemical expression of NEDD9 and E-cadherin as markers of metastatic potential using a tissue microarray. This retrospective study included 40 previously untreated patients, including 23 males and 17 females with a median age of 64.5 years (range 38–84), with colorectal cancer and synchronous liver metastases that underwent simultaneous colorectal and hepatic resection between January 1st 2006 and December 31st 2013, in the Clinical Hospital Center Sestre Milosrdnice (Zagreb, Croatia). The most frequent tumor stage was T3, while the most frequent nodal stage was N1. Microvascular invasion was present in 37.5% of patients, while perineural invasion was observed in 30% of patients. The immunohistochemical staining index of E-cadherin was highly positive in 87.5% samples of colorectal cancer, 67.7% of lymph nodes and 77.5% of liver metastases. In the primary tumor, highly positive NEDD9 expression was identified in 22.5% of patients. In lymph nodes, it was identified in 35.5% of patients, while in the liver, it was identified in 30% of patients. Significant positive correlations were observed between the percentage of positive lymph nodes and the immunohistochemical staining index of E-cadherin (ρ=0.372; P=0.039) and NEDD9 (ρ=0.451; P=0.011) in lymph nodes. After the conclusion of the study, 55% of the patients succumbed. No significant differences in survival rates were identified regarding the expression of E-cadherin and NEDD9 in the primary tumor, metastatic lymph nodes and liver metastases. Due to the small sample size and the negative results obtained, further research is required to implement these parameters as prognostic factors.
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Affiliation(s)
- Petra Jurčić
- Department of Radiotherapy and Medical Oncology, University Hospital for Tumors, Clinical Hospital Center Sestre Milosrdnice, Zagreb 10000, Croatia
| | - Petra Radulović
- Ljudevit Jurak Department of Pathology and Cytology, University Hospital for Tumors, Clinical Hospital Center Sestre Milosrdnice, Zagreb 10000, Croatia
| | - Melita Perić Balja
- Department of Oncological Pathology, University Hospital for Tumors, Clinical Hospital Center Sestre Milosrdnice, Zagreb 10000, Croatia
| | - Milan Milošević
- Department for Environmental and Occupational Health, University of Zagreb, School of Medicine, Andrija Štampar School of Public Health, Zagreb 10000, Croatia
| | - Božo Krušlin
- Ljudevit Jurak Department of Pathology and Cytology, University Hospital for Tumors, Clinical Hospital Center Sestre Milosrdnice, Zagreb 10000, Croatia.,School of Medicine, University of Zagreb, Zagreb 10000, Croatia
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Choi JE, Bae JS, Kang MJ, Chung MJ, Jang KY, Park HS, Moon WS. Expression of epithelial-mesenchymal transition and cancer stem cell markers in colorectal adenocarcinoma: Clinicopathological significance. Oncol Rep 2017; 38:1695-1705. [DOI: 10.3892/or.2017.5790] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2017] [Accepted: 06/16/2017] [Indexed: 11/05/2022] Open
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Xia J, Cheng Y, Zhang H, Li R, Hu Y, Liu B. The role of adhesions between homologous cancer cells in tumor progression and targeted therapy. Expert Rev Anticancer Ther 2017; 17:517-526. [DOI: 10.1080/14737140.2017.1322511] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
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Loss of E-cadherin promotes migration and invasion of cholangiocarcinoma cells and serves as a potential marker of metastasis. Tumour Biol 2014; 35:8645-52. [PMID: 24867095 DOI: 10.1007/s13277-014-2087-6] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2013] [Accepted: 05/12/2014] [Indexed: 12/21/2022] Open
Abstract
Tumor progression is characterized by loss of cell adhesion and increase of invasion and metastasis. E-cadherin, a cell adhesion molecule, is frequently downregulated and has been proposed as an important mediator in epithelial-mesenchymal transition (EMT) in tumors. In this study, we investigated the expression of E-cadherin and its association with cancer invasion and prognosis in cholangiocarcinoma (CCA). Immunohistochemistry results demonstrated a statistically significant association between the positive metastasis status with low E-cadherin protein expression in human CCA tissues (P = 0.04). Statistical trends were identified for low E-cadherin level and shorter survival time (P = 0.08). Targeting the E-cadherin expression in CCA cells with siRNA caused upregulation of vimentin, a mesenchymal marker, and disappearance of the E-cadherin/β-catenin adhesion complex from cell membranes. Moreover, migration and invasion abilities of the cells were increased under this condition. These findings suggest that reduction of E-cadherin contributes to CCA progression by attenuating the strength of cellular adhesion, which affects motility as well as regulating the expression of EMT-related genes during CCA invasion and metastasis. Thus, E-cadherin can act as a central modulator of tumor cell phenotype and is a potential metastasis marker in CCA.
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Kroepil F, Fluegen G, Totikov Z, Baldus SE, Vay C, Schauer M, Topp SA, Esch JSA, Knoefel WT, Stoecklein NH. Down-regulation of CDH1 is associated with expression of SNAI1 in colorectal adenomas. PLoS One 2012; 7:e46665. [PMID: 23029563 PMCID: PMC3460919 DOI: 10.1371/journal.pone.0046665] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2012] [Accepted: 09/03/2012] [Indexed: 12/13/2022] Open
Abstract
INTRODUCTION Down-regulation of E-cadherin (CDH1) and epithelial-mesenchymal transition (EMT) are considered critical events for invasion and metastasis of colorectal carcinoma. Here we tested whether the important regulators of E-cadherin expression SNAI1 and TWIST1 are already detectable in human colorectal adenomas. METHODS RNA was extracted from a set of randomly selected formalin-fixed and paraffin-embedded (FFPE) colorectal adenomas (n = 41) and normal colon mucosa (n = 10). Subsequently mRNA expression of CDH1, CDH2, SNAI1 and TWIST1 was analysed by quantitative RT-PCR analysis. CDH1 as well as SNAI1 protein expression were assessed by immunohistochemistry (IHC). RESULTS SNAI1 mRNA was expressed in 78% (n = 32/41), TWIST1 mRNA in 41% (n = 17/41) and CDH2 mRNA in 41% (n = 17/41) of the colorectal adenoma tissue, while normal colon mucosa was negative for these transcription factors. We found a significant correlation between reduced CDH1 and the presence of SNAI1 mRNA expression and for combined SNAI1 and TWIST1 mRNA expression, respectively. A correlation between CDH2 mRNA expression and reduced CDH1 expression was not observed. We confirmed the relationship between SNAI1 expression and reduced E-cadherin expression on the protein level via IHC. CONCLUSION Our data show that SNAI1 and Twist1 are already expressed in benign precursor lesions of colorectal cancer and that SNAI1 expression was significantly correlated with lower expression of CDH1. Whether these findings reflect true EMT and/or are a sign of a more aggressive biology need to be investigated in further studies.
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Affiliation(s)
- Feride Kroepil
- Department of General-, Visceral- and Pediatric Surgery, University Hospital Düsseldorf, Düsseldorf, Germany
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Buda A, Pignatelli M. E-cadherin and the cytoskeletal network in colorectal cancer development and metastasis. ACTA ACUST UNITED AC 2011; 18:133-43. [PMID: 22176698 DOI: 10.3109/15419061.2011.636465] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Abnormalities in the expression and functional activity of cell adhesion molecules are implicated in the development and progression of the majority of colorectal cancers (CRC). Cell-cell adhesion molecule E-cadherin regulates cell polarity, differentiation, proliferation and migration through its intimate association to the actin cytoskeletal network. During colorectal carcinogenesis changes in intercellular adhesion and dynamic rearrangements in the actin cytoskeleton result in altered signalling and migration with loss of contact inhibition. The adenomatous polyposis coli (APC) protein, besides its established role in the β catenin/Wnt signalling pathway, can coordinate microtubule and actin organization during cell migration. The actin-bundling protein Fascin promotes cell motility and is overexpressed in CRC. Based on recent molecular and pathological studies, this review focusses on the role of these molecules sharing the common feature of being associated with the cytoskeletal network during colorectal carcinogenesis and metastasis. The potential use of these molecules as prognostic markers and/or therapeutic targets will also be discussed.
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Affiliation(s)
- Andrea Buda
- School of Clinical Sciences, University of Bristol, Bristol, UK
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Losi L, Parenti S, Ferrarini F, Rivasi F, Gavioli M, Natalini G, Ferrari S, Grande A. Down-regulation of μ-protocadherin expression is a common event in colorectal carcinogenesis. Hum Pathol 2011; 42:960-71. [PMID: 21315419 DOI: 10.1016/j.humpath.2010.10.009] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2010] [Revised: 10/22/2010] [Accepted: 10/27/2010] [Indexed: 11/25/2022]
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Banu NA, Daly RS, Buda A, Moorghen M, Baker J, Pignatelli M. Reduced tumour progression and angiogenesis in 1,2-dimethylhydrazine mice treated with NS-398 is associated with down-regulation of cyclooxygenase-2 and decreased beta-catenin nuclear localisation. ACTA ACUST UNITED AC 2011; 18:1-8. [PMID: 21679035 DOI: 10.3109/15419061.2011.586754] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Cyclooxygenase (COX)-2 is a key molecular target of colon cancer prevention. However, the mechanisms by which COX-2 inhibitors confer protective effects against tumour development are not completely understood. The aim of this study was to elucidate the effects of NS-398 in the 1,2-dimethylhydrazine (DMH) mouse model with respect to alteration in the expression of COX-2 and E-cadherin-catenin complex. Alterations in cell proliferation, apoptosis, and vascular density were investigated. NS-398 showed reduced COX-2 immunoreactivity in adenomas with a decrease in vascular density in non-dysplastic mucosa. Adenomas revealed increased E-cadherin and beta-catenin reactivity. NS-398 reduced the percentages of tumour cells with nuclear localisation of beta-catenin and cyclin D1. Bromodeoxyuridine (BrdUrd) index in adenomas was significantly higher in untreated animals. NS-398 resulted in significant increase in apoptosis in adenomas. Our results suggest a protective role of NS-398 on tumour development associated with reduced COX-2 expression, reduced vascular density and perturbation of beta-catenin signalling pathway.
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Affiliation(s)
- Nahida A Banu
- Division of Histopathology, School of Cellular and Molecular Medicine, Medical Sciences Building and Bristol Royal Infirmary, University Hospitals, Bristol NHS Foundation Trust, University of Bristol , UK
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Filiz AI, Senol Z, Sucullu I, Kurt Y, Demirbas S, Akin ML. The survival effect of E-cadherin and catenins in colorectal carcinomas. Colorectal Dis 2010; 12:1223-30. [PMID: 19575736 DOI: 10.1111/j.1463-1318.2009.01994.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/07/2022]
Abstract
AIM The E-cadherin/catenin complex plays an important role in epithelial tissue architecture. Decreased expression of cell adhesion molecules (E-cadherin, α-, β- and γ-catenin) have been reported to correlate with invasive behaviour. The aim of this study was to investigate the relation between the expression of adhesion molecules and clinicopathological characteristics and survival in colorectal carcinoma. METHOD The expression of adhesion molecules were studied by immunohistochemistry in 138 colorectal carcinomas. RESULTS The mean age of the patients was 65 years (range: 21-89 years). In primary carcinomas, a reduction in membranous expression of E-cadherin, α-catenin, β-catenin, γ-catenin was demonstrated (70%, 68%, 73%, 77%, respectively). Nuclear expression of β-catenin was found in eight (5%) patients. Decreased membranous β- and γ-catenin expression significantly correlated with tumour differentiation (P = 0.013, P = 0.03, respectively). There was a significant association between advanced stage of the tumour and decreased membranous α-catenin expression (P = 0.012). Decreased E-cadherin and β-catenin membranous expression correlated with short survival following curative resection of the primary tumour (P = 0.04, P = 0.03, respectively). CONCLUSION The decreased membranous expression of E-cadherin and β-catenin and increased cytoplasmic expression of β-catenin might be used as a prognostic marker to monitor patients with colorectal cancer.
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Affiliation(s)
- A I Filiz
- Department of General Surgery, Gulhane Military Medical Academy, Uskudar, Istanbul, Turkey.
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Truant SC, Gouyer VP, Leteurtre EA, Zerimech F, Huet GM, Pruvot FRR. E-cadherin and beta-catenin mRNA levels throughout colon cancer progression. J Surg Res 2008; 150:212-8. [PMID: 18316097 DOI: 10.1016/j.jss.2007.12.800] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2007] [Revised: 12/10/2007] [Accepted: 12/19/2007] [Indexed: 12/01/2022]
Abstract
BACKGROUND Although E-cadherin and beta-catenin are key regulators in tumor invasion and proliferation, few studies have been undertaken on the expression of these genes at the messenger ribonucleic acid (mRNA) level in relation to the progression of colon cancer. PATIENTS AND METHODS In this study, tissue samples from colectomy (n = 37) or hepatectomy (n = 23) were collected in both tumor and adjacent normal tissues. Real-time quantitative reverse transcriptase-polymerase chain reaction was used to quantify E-cadherin and beta-catenin mRNAs in reference to 18S RNA. RESULTS E-cadherin and beta-catenin levels in colon carcinomas were not statistically different compared with adjacent normal mucosa and were not correlated with tumor, nodes, and metastases (TNM) stage. Conversely, E-cadherin and beta-catenin levels were significantly higher in liver metastases than in adjacent normal tissue. Interestingly, we found that E-cadherin level in liver metastases was correlated to the TNM stage of the related primary tumor: a higher E-cadherin level was found for State I-II TNM. In addition, a high expression of E-cadherin in liver metastases was associated with a lower occurrence of extra-hepatic metastases after resection of liver metastases. CONCLUSION Taken together, these data show that E-cadherin and beta-catenin expressions are regulated throughout colon cancer progression.
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Affiliation(s)
- Stéphanie C Truant
- Department of Digestive Surgery and Transplantation, University Hospitals, Lille, France.
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Mahomed F, Altini M, Meer S. Altered E-cadherin/?-catenin expression in oral squamous carcinoma with and without nodal metastasis. Oral Dis 2007; 13:386-92. [PMID: 17577324 DOI: 10.1111/j.1601-0825.2006.01295.x] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
OBJECTIVES The aim of this study was to investigate the potential use of E-cadherin, a tumour-suppressor gene product involved in establishing cell-cell adhesion and one of its associated proteins, beta-catenin, as markers of nodal metastasis in oral squamous cell carcinoma (OSCC). MATERIALS AND METHODS Thirty invasive OSCCs in patients with (n = 19) and without (n = 11) nodal metastases, as confirmed on histopathologic examination of the resected regional lymph nodes (n = 30), were examined for E-cadherin and beta-catenin expression by immunohistochemistry. RESULTS There was a highly significant association (P < 0.0001) between E-cadherin and beta-catenin expression and tumour differentiation by conventional Broders' grading of the whole tumour. Irrespective of the nodal status and invasive tumour front (ITF) grading score, however, loss of expression was recorded at the ITF in 28 (93%) of 30 tumours and 22 (73%) of 30 tumours stained for E-cadherin and beta-catenin respectively. CONCLUSION The results of this study suggest an association between loss of expression of E-cadherin and beta-catenin and a lower degree of differentiation; however, their use as markers of nodal metastasis in OSCC appears unreliable.
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Affiliation(s)
- F Mahomed
- Division of Oral Pathology, School of Oral Health Sciences, University of Witwatersrand, Johannesburg, South Africa.
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Elzagheid A, Algars A, Bendardaf R, Lamlum H, Ristamaki R, Collan Y, Syrjanen K, Pyrhonen S. E-cadherin expression pattern in primary colorectal carcinomas and their metastases reflects disease outcome. World J Gastroenterol 2006; 12:4304-9. [PMID: 16865770 PMCID: PMC4087739 DOI: 10.3748/wjg.v12.i27.4304] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
AIM: To investigate the changes that occur in E-cadherin expression during the process of metastasis in colorectal cancer.
METHODS: E-cadherin expression was detected by immunohistochemistry and two indices of expression were calculated which reflected the level of expression and the locations (membrane and cytoplasm). Univariate and multivariate survival analyses were used to assess the value of these two E-cadherin indices as predictors of both disease-free (DFS) and disease-specific (DSS) survival.
RESULTS: E-cadherin membrane index (MI), but not cytoplasmic index (CI), was significantly higher in primary tumors than their metastases (P = 0.0001). Furthermore, both primary tumor MI and CI were higher among the patients who developed subsequent metastasis (P = 0.022 and P = 0.007, respectively). Interestingly, both indices were higher in liver metastase compared to other anatomic sites (MI, P = 0.034 and CI, P = 0.022). The CI of the primary tumors was a significant predictor of DFS (P = 0.042, univariate analysis), with a strong inverse correlation between CI and DFS (P = 0.006, multivariate analysis). Finally, the MI of primary tumor proved to be a significant independent predictor of DSS, with higher indices being associated with a more favorable outcome (P = 0.016).
CONCLUSION: Examination of E-cadherin expression and distribution in colorectal tumors can be extremely valuable in predicting disease recurrence. The observation that aberrant cytoplasmic expression of E-cadherin can predict disease recurrence is obviously of great importance for both patients and clinicians, and significantly affects decisions concerning the therapy and management of the patients.
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Affiliation(s)
- Adam Elzagheid
- Department of Oncology and Radiotherapy, Turku University Hospital, Savitehtaankatu 1 PB 52, FIN-20520 Turku, Finland.
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Kartenbeck J, Haselmann U, Gassler N. Synthesis of junctional proteins in metastasizing colon cancer cells. Eur J Cell Biol 2005; 84:417-430. [PMID: 15819418 DOI: 10.1016/j.ejcb.2005.01.005] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Various authors have reported reduced synthesis of epithelial junctional proteins during dedifferentiation, tumorigenesis and metastasis in a great variety of tumors. Consequently, it is generally accepted that loss of adhesive molecules and adhesion structures is implicated in the development of an invasive phenotype and poor patient prognosis. Colon carcinomas, on the other hand, were shown to behave differently as synthesis of main adhesive proteins continues despite the development of an invasive phenotype. In this study we used cultured cells grown under conditions that inhibited intercellular adhesion (low Ca2+ concentration) and compared these results with data obtained from metastasizing colon cancer cells (signet ring cell carcinoma). Characterization of these proteins and their structures were performed by immunoprecipitations, Western blot analysis, immunohistochemistry, pre-embedding immuno-electron microscopy, and a new method to perform immuno-electron microscopy on paraffin-embedded material, which we present in this paper. We demonstrate that synthesis carries on for both, the desmosomal and the proteins of the zonula adhaerens. While, however, the assembly of desmosomal structures in the form of half-desmosomes at the cell surface continues, those of the zonula adhaerens did not. Instead E-cadherin was found, although associated with alpha-catenin, beta-catenin, and plakoglobin, evenly distributed at the plasma membrane of the cultured cells and also at the surface of the dissociated tumor cells. We conclude from our observations that continued expression and synthesis of junctional proteins do not necessarily contribute to the suppression of tumor invasion and metastasis of colon cancer.
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Affiliation(s)
- Jürgen Kartenbeck
- Division of Cell Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
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El-Hariry I, Pignatelli M. Adhesion molecules: opportunities for modulation and a paradigm for novel therapeutic approaches in cancer. Expert Opin Investig Drugs 2005; 6:1465-78. [PMID: 15989513 DOI: 10.1517/13543784.6.10.1465] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
In the past decade, there have been major advances in the elucidation of processes underlying tumour invasion and metastasis, in which adhesion molecules play a critical role. These advances have revolutionised our ability to devise novel approaches for cancer treatment. This review gives an insight into the adhesion pathways, and highlights the current status of adhesion molecules as potential therapeutic targets.
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Affiliation(s)
- I El-Hariry
- Cell Adhesion Laboratory, Department of Histopathology, Royal Postgraduate Medical School, Hammersmith Hospital, Du Cane Road, London, W12 ONN, UK
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Khoursheed MA, Mathew TC, Makar RR, Louis S, Asfar SK, Al-Sayer HM, Dashti HM, Al-Bader A. Expression of E-cadherin in human colorectal cancer. Surgeon 2005; 1:86-91. [PMID: 15573626 DOI: 10.1016/s1479-666x(03)80121-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
AIM To investigate the expression of E-cadherin, a calcium-dependent cell-cell adhesion molecule in colorectal carcinoma. Antibodies to E-Cadherin were used to establish the association of their expression with the clinicopathological characteristics of this disease using immunohistochemical methods. METHODS Immunohistochemical analysis for E-cadherin was carried out in formalin-fixed, paraffin-embedded sections of neoplastic colorectal tissues and non-neoplastic ones adjacent to the lesion from 49 patients who underwent surgery, by the standard peroxidase-antiperoxidase method. Expression of this antigen in normal and malignant epithelium and stromal cells was compared. RESULTS Both neoplastic and normal tissues showed expression of E-cadherin. There was, however, higher expression of E-cadherin in epithelial cells in both tumour and normal tissues than stromal cells. The percentage of expression in epithelial cells of well-differentiated tumours was significantly higher than moderately differentiated tumours. Loss of normal membranous expression and the presence of cytoplasmic and mixed staining were found frequently in tumour tissues (p = 0.004). This loss of membranous expression, however, did not correlate with Duke's staging, tumour grade, sex, size or site of the tumour. CONCLUSION This study suggests that the lower expression of E-cadherin in less differentiated tumours may explain their aggressive nature, although loss of membranous expression was not significantly correlated to Duke's staging, tumour grade, sex, size and site of tumour.
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Affiliation(s)
- M A Khoursheed
- Department of Surgery, Faculty of Medicine, Kuwait University, PO Box 24923, Safat 13110, Kuwait
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Escaffit F, Perreault N, Jean D, Francoeur C, Herring E, Rancourt C, Rivard N, Vachon PH, Paré F, Boucher MP, Auclair J, Beaulieu JF. Repressed E-cadherin expression in the lower crypt of human small intestine: a cell marker of functional relevance. Exp Cell Res 2005; 302:206-20. [PMID: 15561102 DOI: 10.1016/j.yexcr.2004.08.033] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2004] [Revised: 08/27/2004] [Indexed: 11/28/2022]
Abstract
In epithelia, abnormal expression of E-cadherin is related to pathologies involving a loss of cell polarization and/or differentiation. However, recent observations suggest that E-cadherin could also be repressed under physiological conditions, such as in some epithelial stem cell lineages. In the present work, we have analyzed E-cadherin expression in human intestinal epithelial cell progenitors and investigated its potential role. E-cadherin expression was analyzed along the crypt-villus axis by immunofluorescence on cryosections of small intestine. E-cadherin was found to be differentially expressed, being significantly weaker in the cells located at the bottom of the crypts. Surprisingly, neither the E-cadherin protein nor transcript were detected in a normal human intestinal epithelial (HIEC) crypt cell model isolated in our laboratory, whereas other E-cadherin-related components such as catenins and APC were present. Forced expression of E-cadherin in HIEC cells increased membrane-associated beta-catenin and was accompanied by the appearance of junction-like structures at the cell-cell interface. Functionally, cell kinetics and p21Cip levels were found to be altered in the E-cadherin expressing HIEC cells as compared to controls. Furthermore, a significant reduction of the migration abilities and an increase in sensitivity to anoikis were also observed. These results suggest that down-regulated expression of E-cadherin is a human intestinal crypt base cell-related feature that appears to be of functional relevance for the maintenance of the progenitor cell population.
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Affiliation(s)
- Fabrice Escaffit
- Département d'anatomie et de Biologie Cellulaire, Faculté de médecine, Université de Sherbrooke, CIHR Group in Functional Development and Physiopathology of the Digestive Tract, Sherbrooke, Québec, Canada J1H 5N4
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19
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Massarelli E, Brown E, Tran NK, Liu DD, Izzo JG, Lee JJ, El-Naggar AK, Hong WK, Papadimitrakopoulou VA. Loss of E-cadherin and p27 expression is associated with head and neck squamous tumorigenesis. Cancer 2005; 103:952-9. [PMID: 15666322 DOI: 10.1002/cncr.20879] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
BACKGROUND In neoplastic head and neck lesions, it has been found that the loss or reduction in E-cadherin expression is a late event and is associated with invasion. Low p27 levels have been associated with a poor prognosis in many different tumors, including laryngeal carcinoma. The authors investigated p27 and E-cadherin protein expression in the early stages of head and neck tumorigenesis and evaluated their predictive roles individually and in association with carcinogenesis. METHODS Tissue biopsies from 46 patients who were participants in 3 chemoprevention trials were analyzed for E-cadherin expression, and 40 samples were analyzed for p27 expression using immunohistochemistry. RESULTS The data suggested that loss of both E-cadherin expression and p27 expression occurred early during the preneoplastic steps of head and neck carcinogenesis, and loss of p27 protein expression alone (P=0.02) and in combination with loss of E-cadherin expression (P=0.04) was a significant predictor of the risk for head and neck carcinoma. CONCLUSIONS The loss of p27 expression may be useful in the construction of a risk model for head and neck carcinogenesis and may represent a potential target for chemopreventive interventions. Longer follow-up of the high percentage of low-risk preneoplastic lesions in the current study and validation in a larger sample size may be required to establish the predictive role of these abnormalities.
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Affiliation(s)
- Erminia Massarelli
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA
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20
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Jungck M, Grünhage F, Spengler U, Dernac A, Mathiak M, Caspari R, Friedl W, Sauerbruch T. E-cadherin expression is homogeneously reduced in adenoma from patients with familial adenomatous polyposis: an immunohistochemical study of E-cadherin, beta-catenin and cyclooxygenase-2 expression. Int J Colorectal Dis 2004; 19:438-45. [PMID: 14986031 DOI: 10.1007/s00384-003-0575-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/03/2003] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND AIMS The adenomatous polyposis coli (APC) protein plays a crucial role in the regulation of beta-catenin, which is linked to the cell adhesion molecule E-cadherin. Furthermore, beta-catenin and cyclooxygenase-2 (COX-2) are both involved in the activation of nuclear transcription factors inducing cell proliferation. Germline mutations in the APC gene are the cause of familial adenomatous polyposis (FAP). To characterise the expression pattern of these proteins in FAP in comparison with sporadic adenomas, we studied 18 FAP-associated adenomas, 16 sporadic adenomas and seven normal colonic controls. METHODS E-cadherin, beta-catenin, COX-2 expression and the proliferative index (Ki67) were assessed by immunohistochemistry (index of expressing cells / total number of cells) in adenomatous mucosa, adjacent non-neoplastic tissue and normal colonic controls. RESULTS E-cadherin expression was significantly and homogeneously reduced in FAP adenomas (24%; 95%CI 16-32; sporadic adenomas 61%; 38-84; normal controls 98%; 96-100). Membraneous beta-catenin expression was significantly reduced in both FAP (30%; 11-49) and sporadic (42%; 19-65) adenomas (normal controls 96%; 88-104), whereas marked nuclear staining occurred in sporadic, but not in FAP adenomas. Stromal COX-2 expression and the proliferative index were increased only in sporadic adenomas (sporadic adenomas: COX-2 12%; 7-17, Ki67 24%; 15-33, FAP adenomas: COX-2 8%; 5-11, Ki67 5%; 2-9, normal controls: COX-2 4%; 2-7, Ki67 6%; 1-11). CONCLUSION Proteins involved in cell adhesion and cell proliferation, especially E-cadherin, are expressed differently in FAP and sporadic adenoma, pointing to possible differences in the molecular pathways to adenoma.
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Affiliation(s)
- M Jungck
- Department of Internal Medicine I, University Hospital Bonn, Sigmund-Freud-Strasse 25, Bonn, Germany.
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21
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Rosivatz E, Becker I, Bamba M, Schott C, Diebold J, Mayr D, Höfler H, Becker KF. Neoexpression of N-cadherin in E-cadherin positive colon cancers. Int J Cancer 2004; 111:711-9. [PMID: 15252840 DOI: 10.1002/ijc.20317] [Citation(s) in RCA: 59] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
In our study, we aimed to investigate the expression of N-cadherin and E-cadherin and their dependency on epithelial-mesenchymal transition regulators SNAI1, SIP1 and TWIST in human colon cancer. Expression of E-cadherin and N-cadherin was examined by immunohistochemistry in 80 colon carcinomas by using paraffin embedded and formalin fixed tissues. Those cases were partly analyzed for mRNA expression of N-cadherin (42 cases), TWIST (18 cases), SNAI1 (25 cases) and SIP1 (25 cases) by real-time quantitative RT-PCR. Additionally, colon carcinomas that showed amplification of 20q13, the localization of the human SNAI1 gene, were examined. We found cytoplasmic and/or membrane-associated immunoreactivity of N-cadherin in 35/80 (44%) of the cases. However, there was no correlation to upregulated TWIST mRNA levels, as we have shown previously for diffuse-type gastric cancers with abnormal N-cadherin expression. Reduced and/or cytoplasmic E-cadherin immunoreactivity was detected in 19% (15/80) of the cases. Expression of SNAI1 or SIP1 mRNA was not seen in any of the 25 cases analyzed. There was no correlation between amplification of 20q13 and SNAI1 mRNA expression. Remarkably, N-cadherin was almost exclusively expressed in those cases showing normal E-cadherin immunoreactivity, suggesting a mutual exclusion between abnormal E-cadherin reduction and upregulation of N-cadherin. For the first time, we postulate a role for N-cadherin in primary colon cancer progression, which may be similar to the effect discovered by others in breast cancer cell lines, where coexpressed N-cadherin can exert a dominant function over E-cadherin's adhesive function and thus promote tumor invasiveness.
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22
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Xie D, Sham JST, Zeng WF, Lin HL, Che LH, Wu HX, Wen JM, Fang Y, Hu L, Guan XY. Heterogeneous expression and association of beta-catenin, p16 and c-myc in multistage colorectal tumorigenesis and progression detected by tissue microarray. Int J Cancer 2004; 107:896-902. [PMID: 14601048 DOI: 10.1002/ijc.11514] [Citation(s) in RCA: 88] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Most colorectal carcinomas (CRCs) arise from adenomas through an archetypal pathogenic pathway, the adenoma-carcinoma-metastasis sequence. Aberrant expression of beta-catenin, p16, E-cadherin and c-myc appears to have played important roles in the development and/or progression of CRC, but their precise distribution pattern and associations in different pathologic loci along CRC's pathogenic pathway have not been thoroughly examined. In this study, a tissue microarray (TMA) containing 85 advanced CRCs in different Dukes stages was constructed. In each of 85 cases, tissue specimens from normal mucosa and primary carcinomas in different layers of the bowel wall were included in the TMA. Tissue specimens from matched adenoma, lymph node metastases and distant metastases were obtained from 22, 21 and 21 cases, respectively. Expression patterns of beta-catenin, p16, E-cadherin and c-myc were evaluated by immunohistochemistry. The results revealed that nuclear expression of beta-catenin, p16 and c-myc was quantitatively increased from normal mucosa to premalignant adenoma, primary carcinoma and lymph node metastatic carcinoma; the frequency of nuclear overexpression of beta-catenin and p16 in lymph node metastases was significantly higher than that in distant metastases (p < 0.05). These results suggest an association between nuclear overexpression of beta-catenin and/or p16 and CRC lymph node metastasis but not distant metastasis. The results also showed that correlative high nuclear expression of beta-catenin and c-myc was observed in primary carcinomas involving the serosa and lymph node metastases (p < 0.05) but not in other pathologic regions of CRCs, suggesting that the tumor microenvironment in different pathologic loci of colorectal tumorigenesis and progression may influence c-myc responsiveness to beta-catenin/Tcf activation.
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Affiliation(s)
- Dan Xie
- Department of Clinical Oncology, 1/F Building, School of Chinese Medicine, University of Hong Kong, 10 Sassoon Road, Hong Kong, China
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23
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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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Johnston N, Bulmer D, Gill GA, Panetti M, Ross PE, Pearson JP, Pignatelli M, Axford SE, Dettmar PW, Koufman JA. Cell biology of laryngeal epithelial defenses in health and disease: further studies. Ann Otol Rhinol Laryngol 2003; 112:481-91. [PMID: 12834114 DOI: 10.1177/000348940311200601] [Citation(s) in RCA: 150] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
This is the second annual report of an international collaborative research group that is examining the cellular impact of laryngopharyngeal reflux (LPR) on laryngeal epithelium. The results of clinical and experimental studies are presented. Carbonic anhydrase (CA), E-cadherin, and MUC gene expression were analyzed in patients with LPR, in controls, and in an in vitro model. In patients with LPR, we found decreased levels of CAIII in vocal fold epithelium and increased levels in posterior commissure epithelium. The experimental studies confirm that laryngeal CAIII is depleted in response to reflux. Also, cell damage does occur well above pH 4.0. In addition, E-cadherin (transmembrane cell surface molecules, which have a key function in epithelial cell adhesion) was not present in 37% of the LPR laryngeal specimens. In conclusion, the laryngeal epithelium lacks defenses comparable to those in esophageal epithelium, and these differences may contribute to the increased susceptibility of laryngeal epithelium to reflux-related injury.
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Affiliation(s)
- Nikki Johnston
- Center for Voice Disorders of Wake Forest University, Department of Otolaryngology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157-1034, USA
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25
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Tucker E, Buda A, Janghra B, Cpoad J, Moorghan M, Havler M, Dettmar P, Pignatelli M. Abnormalities of the cadherin-catenin complex in chemically-induced colo-rectal carcinogenesis. Proc Nutr Soc 2003; 62:229-36. [PMID: 12756972 DOI: 10.1079/pns2003217] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Beta-Catenin is a multifunctional protein originally identified as a component of the cadherin cell-cell adhesion complex. It also binds the adenomatous polyposis coli (APC) tumour suppressor which controls beta-catenin cellular levels through its degradation. (beta-Catenin and/or APC mutations result in increased cytoplasmic Beta-catenin and nuclear translocation. The aim of the present study was to examine the expression and cellular localisation of alpha and beta-catenin, p120 and E-cadherin in a chemically-induced mouse model of colo-rectal cancer using 1,2-dimethylhydrazine (DMH). Female Balb/C mice were injected subcutaneously with a solution providing 25 mg DMH base/kg body weight for 17 weeks. Animals were killed and tumours identified in the intestine with a dissecting microscope. Formalin-fixed paraffin-embedded sections of normal and dysplastic colonic mucosa were stained by an indirect avidin-biotin immunohistochemical technique using mouse monoclonal antibodies, and membranous, cytoplasmic and nuclear cellular localisation was assessed by light microscopy. Staining distribution scored as follows: 3, > 90 % positive epithelial cells; 2, >50 % positive epithelial cells; 1, <50 % positive epithelial cells. Non-dysplastic colonic epithelial cells revealed beta-catenin expression at the membrane (33/41 scored 3),areas of cytoplasmic expression (24/41 scored 1) and no nuclear staining. Dysplastic colonic epithelium revealed increased membranous and cytoplasmic, beta-catenin immunoreactivity (39/41 and 38/41 both scored 3) with focal nuclear staining (14/41). Expression patterns for ac-catenin, p120, and E-cadherin were similar to beta-catenin with increased membranous and cytoplasmic immunoreactivity in dysplastic mucosa, although no nuclear staining was observed. Increased cytoplasmic expression and nuclear localisation of beta-catenin are consistent with a possible mutation in its gene, and this finding was in keeping with the mutational analysis of exon 3 by single-strand conformational polymorphism. Increased immunoreactivity of the other catenins also suggests further disruption in catenin regulation. In summary, alterations in the beta-catenin expression and cellular localisation in the DMH-induced tumours are similar to those seen inhuman sporadic colorectal tumours. The DMH is therefore a useful model for studying the abnormalities of the E-cadherin-catenin pathway in colorectal carcinogenesis.
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Affiliation(s)
- Emma Tucker
- University of Bristol, Department of Pathology and Microbiology, School of Medical Sciences and Bristol Royal Infirmary, Bristol, UK
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26
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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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27
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Ko SCW, Chapple KS, Hawcroft G, Coletta PL, Markham AF, Hull MA. Paracrine cyclooxygenase-2-mediated signalling by macrophages promotes tumorigenic progression of intestinal epithelial cells. Oncogene 2002; 21:7175-86. [PMID: 12370807 DOI: 10.1038/sj.onc.1205869] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2002] [Revised: 07/08/2002] [Accepted: 07/15/2002] [Indexed: 01/09/2023]
Abstract
In human colorectal adenomas or polyps, cyclooxygenase-2 is expressed predominantly by stromal (or interstitial) macrophages. Therefore, we tested the hypothesis that macrophage cyclooxygenase-2 has paracrine pro-tumorigenic activity using in vitro models of macrophage-epithelial cell interactions. We report that macrophages can promote tumorigenic progression of intestinal epithelial cells (evidenced by decreased cell-cell contact inhibition, increased proliferation and apoptosis, gain of anchorage-independent growth capability, decreased membranous E-cadherin expression, up-regulation of cyclooxygenase-2 expression, down-regulation of transforming growth factor-beta type II receptor expression and resistance to the anti-proliferative activity of transforming growth factor-beta(1)) in a paracrine, cyclooxygenase-2-dependent manner. Pharmacologically relevant concentrations (1-2 microM) of a selective cyclooxygenase-2 inhibitor had no detectable, direct effect on intestinal epithelial cells but inhibited the macrophage-epithelial cell signal mediating tumorigenic progression. Cyclooxygenase-2-mediated stromal-epithelial cell signalling during the early stages of intestinal tumorigenesis provides a novel target for chemoprevention of colorectal cancer (and other gastro-intestinal epithelial malignancies, which arise on a background of chronic inflammation, such as gastric cancer) and may explain the discrepancy between the concentrations of cyclooxygenase inhibitors required to produce anti-neoplastic effects in vitro and in vivo.
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Affiliation(s)
- Stanley C W Ko
- Molecular Medicine Unit, University of Leeds, St James's University Hospital, Leeds LS9 7TF, UK
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28
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El-Bahrawy MA, Talbot IC, Poulsom R, Jeffery R, Alison MR. The expression of E-cadherin and catenins in colorectal tumours from familial adenomatous polyposis patients. J Pathol 2002; 198:69-76. [PMID: 12210065 DOI: 10.1002/path.1168] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Familial adenomatous polyposis patients (FAP) harbour a germline mutation of the adenomatous polyposis coli gene (APC), and APC mutations are early events in the development of sporadic colorectal neoplasms. The APC protein interacts with beta-catenin and gamma-catenin and APC mutations are believed to play a role in the altered levels of beta-catenin in colorectal tumours. Immunohistochemical studies have shown changes in the expression and distribution of E-cadherin and catenins in sporadic colorectal neoplasms. This study assessed the expression and distribution of E-cadherin and catenins in colorectal neoplasms and non-neoplastic mucosa from FAP patients. The expression and cellular distribution of E-cadherin and catenins were studied by immunohistochemistry in 61 adenomas, five carcinomas, and non-neoplastic mucosa from 18 FAP patients. mRNA levels in the carcinomas were studied by in situ hybridization. The expression of E-cadherin and catenins was increased in over 80% of the adenomas, with evident cytoplasmic immunoreactivity. There was increased expression of E-cadherin and catenin in the carcinomas, with a notable increase in the levels of mRNA, in comparison with the non-neoplastic mucosa.
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Abstract
E-cadherin and its associated cytoplasmic proteins including alpha-, beta-, and gamma-catenin play a pivotal role in the maintenance of normal tissue architecture and the suppression of cancer invasion. The purpose of this study was to evaluate the expression of E-cadherin and alpha-, beta-, and gamma-catenin in a larger sample of early gastric cancer, and to examine the relation between these expressions and various clinicopathologic variables. The expression of E-cadherin and alpha-, beta-, and gamma-catenin was investigated using immunohistochemical technique with formalin-fixed, paraffin-embedded tissue specimens obtained from 108 patients who underwent surgery for early gastric cancer. In the gastric mucosa of noncancerous areas, epithelial cells showed equally strong membranous expression of E-cadherin and alpha-, beta-, and gamma-catenin proteins at the cell-cell boundaries. Reduced expression of E-cadherin and alpha-, beta-, and gamma-catenin was demonstrated in 43.5%, 39.8%, 42.6%, and 50% of cancer tissues, respectively. Whereas 34 tumors (31.5%) displayed preserved expression of all four E-cadherin-catenin complex components, 21 tumors (19.4%) displayed reduced expression of all components of this complex. Reduced expression of E-cadherin and alpha- and gamma-catenin occurred more frequently in diffuse than in intestinal types of cancer, and decreased expression of E-cadherin and alpha-, beta-, and gamma-catenin correlated with poor differentiation. The expression of E-cadherin and beta- and gamma-catenin did not correlate with the patient's age, gender, tumor size, location, macroscopic type, depth of invasion, or lymph node metastasis. Only reduced expression of alpha-catenin correlated with lymph node metastasis. Reduced expression of all four E-cadherin-catenin complex components correlated with poorly differentiated and diffuse-type cancers, but not with the patient's age, gender, tumor size, location, macroscopic type, depth of invasion, or lymph node metastasis. These results suggest that dysfunction of the E-cadherin-catenin complex occurs in an early stage of carcinogenesis, playing a crucial role in disruption of tissue architecture and loss of differentiation in early gastric cancer.
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Affiliation(s)
- Young-Eun Joo
- Department of Internal Medicine, Chonnam National University Medical School, Kwangju, Korea.
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Bremnes RM, Veve R, Hirsch FR, Franklin WA. The E-cadherin cell-cell adhesion complex and lung cancer invasion, metastasis, and prognosis. Lung Cancer 2002; 36:115-24. [PMID: 11955645 DOI: 10.1016/s0169-5002(01)00471-8] [Citation(s) in RCA: 165] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND Lung cancer is the most common cause of cancer deaths in the western world. Progress in treatment results has been limited, and the prognosis is poor with a 5-year survival less than 15%. Based on new developments in molecular biology, our knowledge about lung carcinogenesis and mechanisms for invasion and metastasis has expanded and may in the future lead to more specific targeted therapies and better prognosis. The E-cadherin-catenin complex is critical for intercellular adhesiveness and maintenance of normal and malignant tissue architecture. Reduced expression of this complex in malignant disease is associated with tumour invasion, metastasis, and unfavorable prognosis. METHODS This review is based on search in the Medline database from 1991 to 2001. We have reviewed the relevance of the E-cadherin-catenin adhesion complex in malignancy in general and lung cancer in particular. Furthermore, its role as target for specific therapy is discussed. RESULTS Available data indicate that alterations of proteins involved in the E-cadherin-catenin complex are early incidents in cancer development. Reduced or altered expression of one or more of the components in this complex is associated with extended invasive and progressive behavior of cancer cells. Consistently, the E-cadherin-catenin complex appears to be increasingly delicate with regard to cancer prognosis. beta-Catenin, one of the components of the adhesion complex, also plays a significant role in cell signal transduction, gene activation, apoptosis inhibition, and increased cellular proliferation and migration. CONCLUSION Inactivation of the E-cadherin-catenin adhesion complex, induced by genetic and epigenetic events, plays a significant role in multistage carcinogenesis, and seems to be associated with dedifferentiation, local invasion, regional metastasis, and reduced survival in lung cancer.
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Affiliation(s)
- Roy M Bremnes
- Department of Pathology, University of Colorado Cancer Center, Denver, USA.
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Yoo J, Park S, Kang CS, Kang SJ, Kim BK. Expression of E-cadherin and p53 proteins in human soft tissue sarcomas. Arch Pathol Lab Med 2002; 126:33-8. [PMID: 11800644 DOI: 10.5858/2002-126-0033-eoecap] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
OBJECTIVE To investigate the expression of E-cadherin in human soft tissue sarcomas and its potential relationship to p53 alterations. DESIGN Tissue sections of 91 soft tissue sarcomas were analyzed by immunohistochemistry for E-cadherin and p53 proteins. Sixty-one tumors were investigated further by the application of the polymerase chain reaction technique and a direct sequence analysis procedure of exons 5 through 8 in the p53 gene. SETTING Tertiary-care teaching hospital. PATIENTS Ninety-one patients with soft tissue tumor were treated surgically. Thirteen of these patients had tumors with epithelial differentiation. RESULTS E-Cadherin was expressed at the cell-cell boundaries in 11 samples (12%): 9/13 (69%) with and 2/78 (3%) without histologic evidence of epithelial elements. Other sarcomas were completely negative for E-cadherin. Overexpression of p53 was detected in 30 cases (33%), 7 of which also demonstrated mutations in the p53 gene. The frequencies of p53 abnormalities in tumors with and without epithelial components were 8% and 37%, respectively. No association was established between E-cadherin immunoreactivity and p53 abnormalities (P =.13). Tumor grade strongly correlated with p53 alterations (P =.01), but not with E-cadherin expression (P =.07). CONCLUSIONS These data support the involvement of p53 alterations in the pathogenesis of soft tissue sarcomas. The lack of E-cadherin expression in these tumors, with the exception of lesions showing epithelial differentiation, indicates that E-cadherin is not an important factor involved in cell-cell adhesion in sarcomas. It is, however, suggested that E-cadherin may play a role in the development and/or maintenance of epithelial architecture in sarcomas, regardless of p53 status.
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Affiliation(s)
- Jinyoung Yoo
- Department of Pathology, St Vincent's Hospital, Catholic University, Kyungkido, South Korea
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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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Madhavan M, Srinivas P, Abraham E, Ahmed I, Mathew A, Vijayalekshmi NR, Balaram P. Cadherins as predictive markers of nodal metastasis in breast cancer. Mod Pathol 2001; 14:423-7. [PMID: 11353052 DOI: 10.1038/modpathol.3880329] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Adhesion molecules, particularly cadherins play a pivotal role in cancer invasion and metastasis. Because the therapeutic management of tumors with and without nodal metastasis differs considerably, our idea was to identify tumors with metastatic potential. We studied the expression of E-cadherin and P-cadherin immunohistochemically in 51 cases of breast cancer that included 29 node-negative and 22 node-positive cases. Expression of the cadherins was mainly membranous, with cytoplasmic staining in a few lesions. Both E-cadherin and P-cadherin showed significant down-regulation of their expression in node-positive tumors in comparison to node-negative tumors. Logistic regression analysis revealed that the positive expression of E-cadherin and P-cadherin showed low odds ratios of 0.1 and 0.2, respectively, and were statistically significant. On multivariate analysis, both the cadherins were found to be of independent prognostic value. This suggests that cadherin expression could be a marker of nodal metastasis. An observation of interest was that the expression of E-cadherin and P-cadherin were highly correlated (correlation coefficient = 0.5873), which requires further evaluation for confirmation of a common regulatory pathway that could be activated in the early onset of nodal metastasis.
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Affiliation(s)
- M Madhavan
- Division of Cancer Research, Regional Cancer Centre, Trivandrum, Kerala, India
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Rubin MA, Mucci NR, Figurski J, Fecko A, Pienta KJ, Day ML. E-cadherin expression in prostate cancer: a broad survey using high-density tissue microarray technology. Hum Pathol 2001; 32:690-7. [PMID: 11486167 DOI: 10.1053/hupa.2001.25902] [Citation(s) in RCA: 139] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
E-cadherin is a calcium 2+-dependent cell-adhesion molecule that determines epithelial development in the embryo and maintains adult differentiated epithelium and homeostasis. Aberrant or decreased expression has been reported to be associated with prostate carcinoma progression. The degree of E-cadherin expression in prostate cancer remains controversial. Some studies have reported decreased expression of E-cadherin as tumors advance and metastasize. Other studies have not demonstrated this relationship. To address these variations, we undertook a study to systematically evaluate E-cadherin expression in a broad range of prostate tissue. Benign prostate, clinically localized prostate cancer, and hormone-refractory metastatic prostate cancer were analyzed under uniform conditions using high-density tissue microarrays (TMA). Formalin-fixed, paraffin-embedded prostate carcinoma from men with clinically localized prostate carcinoma and autopsy material from men who died of widely metastatic, hormone-refractory prostate carcinoma were arrayed into 6 high-density TMA blocks. Benign and atrophic prostate tissue and high-grade prostatic intraepithelial neoplasia (PIN) were also included from the clinically localized cases. Immunohistochemistry was performed using the immunoglobulin G1 mouse monoclonal antibody (HECD-1; Zymed, San Francisco, CA). Membranous staining was recorded as low (aberrant) or high (normal). E-cadherin expression was considered aberrant if less than 70% of the cells had strong membranous staining. A total of 1,220 prostate TMA samples were analyzed. High (normal) E-cadherin expression was seen in 87% of 757 benign, 80% of 41 high-grade PIN, 82% of 325 prostate carcinoma and 90% of 97 hormone-refractory prostate carcinoma TMA samples. Mean E-cadherin expression was determined for each of the 128 clinically localized prostate cancer cases. Aberrant E-cadherin expression showed a statistical trend toward an association with positive surgical margins (P =.012), higher Gleason score (P =.18), and prostate-specific antigen (PSA) failure (Kaplan-Meier analysis, log-rank P =.09). There was a statistically significant association between aberrant E-cadherin expression and larger tumor size (P =.01). No significant associations were seen with extraprostatic extension and seminal vesicle invasion. The current study shows a broad-spectrum approach to evaluating E-cadherin protein expression in prostate carcinoma. Clinically localized prostate tumors, treated with surgery alone, show a high level of E-cadherin expression. Aberrant expression was identified in tumors with positive surgical margins, higher Gleason score, and a higher rate of PSA failure. However, these trends were not statistically significant. A statically significant association between aberrant E-cadherin expression and larger tumor size was identified. In the metastatic hormone-refractory prostate tumors, E-cadherin expression was vastly expressed, and only rare cases had aberrant expression. Therefore, the findings of this study are most consistent with a transient down-regulation of E-cadherin in localized prostate cancer. Metastatic prostate cancer shows strong E-cadherin expression as determined by anti-E-cadherin antibody HECD-1.
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Affiliation(s)
- M A Rubin
- Departments of Pathology, Surgery-Urology Section, University of Michigan, Ann Arbor, MI 48109-0054, USA
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35
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Chan AO, Lam SK, Chu KM, Lam CM, Kwok E, Leung SY, Yuen ST, Law SY, Hui WM, Lai KC, Wong CY, Hu HC, Lai CL, Wong J. Soluble E-cadherin is a valid prognostic marker in gastric carcinoma. Gut 2001; 48:808-11. [PMID: 11358900 PMCID: PMC1728335 DOI: 10.1136/gut.48.6.808] [Citation(s) in RCA: 69] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Gastric cancer remains a major cause of cancer mortality globally but no good prognostic tumour marker is available. Soluble fragment of E-cadherin protein has been reported to increase in the sera of patients with cancer and recently was found to be elevated in 67% of patients with gastric cancer. AIMS To investigate if serum soluble E-cadherin is a valid prognostic marker in gastric cancer. METHODS Concentrations of soluble E-cadherin from 116 patients with histologically confirmed gastric adenocarcinoma and 40 healthy subjects were measured using an immunoenzymometric method with a commercially available sandwich ELISA kit based on monoclonal antibodies. RESULTS The logarithm of the means of soluble E-cadherin concentration was significantly higher in patients with gastric cancers (mean 3.85 (SD 0.28)) than in healthy subjects (3.71 (0.18)) (p=0.001), and in palliative/conservatively treated cancers (3.91 (0.35)) than in operable cancers (3.78 (0.19)) (p=0.015). The logarithm of the concentrations correlated with tumour size (p=0.032) and carcinoembryonic antigen concentrations (p=0.001). The cut off value calculated from discriminant analysis on operability and inoperability/palliative treatment was 7025 ng/ml. Soluble E-cadherin concentrations higher than this cut off value predicted tumour (T4) depth invasion (p=0.020, confidence interval (CI) 1.008-1.668) and palliative/conservative treatment (p=0.023, CI 1.038-2.514). In contrast, the relative risks for lymph node (N2) metastasis, distant metastasis, and stage III/IV disease were 1.41, 1.33, and 1.55 respectively, despite not reaching statistical significance. CONCLUSION Serum soluble E-cadherin is a potential valid prognostic marker for gastric cancer. A high concentration predicts palliative/conservative treatment and T4 invasion.
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Affiliation(s)
- A O Chan
- Department of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong
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36
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Economopoulou P, Hanby A, Odell EW. Expression of E-cadherin, cellular differentiation and polarity in epithelial salivary neoplasms. Oral Oncol 2000; 36:515-8. [PMID: 11036244 DOI: 10.1016/s1368-8375(00)00043-9] [Citation(s) in RCA: 23] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
To investigate whether expression of E-cadherin correlates with polarised tissue organisation, grade or tumour type in salivary neoplasms, frozen sections from 30 salivary gland neoplasms were stained immunohistochemically for E-cadherin using the antibody HECD-1 and compared to the staining patterns in five samples of normal salivary gland. Lesions with areas of lack of staining were restained at two higher antibody concentrations. Normal salivary gland stained strongly around the periphery of acinar and ductal cells. Neoplasms mostly stained strongly regardless of neoplasm type. Reproducible loss of expression was found only in epithelial cells showing stromal or plasmacytoid (hyaline) differentiation in pleomorphic adenoma. Low- and high- grade mucoepidermoid carcinomas, adenocarcinoma NOS and carcinoma ex pleomorphic adenoma showed focal loss of expression but this was not related to tissue architecture, differentiation or invasiveness. We conclude that the relationship seen between E-cadherin expression and cell polarity/glandular organisation in breast and colon does not appear to exist for salivary gland neoplasms in which the diversity of architectural patterns precludes detection of any simple relationship. E-cadherin expression seems unlikely to be a useful marker for diagnosis or prognosis in salivary neoplasia in general.
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Affiliation(s)
- P Economopoulou
- Head and Neck Cancer Research Programme, Division of Oral Medicine and Pathology, King's College London Dental Institute, Floor 28 Guy's Tower, Guy's Hospital, SE1 9RT, London, UK
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37
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Shibuya Y, Ri S, Umeda M, Yoshikawa T, Masago H, Komori T. Ultrastructural localization of E-cadherin and alpha-/beta-catenin in adenoid cystic carcinoma. Histopathology 1999; 35:423-31. [PMID: 10583557 DOI: 10.1046/j.1365-2559.1999.035005423.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
AIMS To investigate the disturbance of intercellular adhesion in adenoid cystic carcinoma (ACC), we examined the ultrastructural localization of E-cadherin (E-cad), alpha-catenin (alpha-cat) and beta-catenin (beta-cat) in ACC, and compared it with that in the normal labial gland. METHODS AND RESULTS Using immuno-electron microscopy, in the normal labial gland, E-cad was found to be uniformly distributed along the plasmalemma, where cells were in close contact with each other, with junctional complexes, desmosomes and interdigitations; expression of alpha-cat and beta-cat was also detected. In ACC, which was classified into tubular, cribriform and trabecular types, E-cad expression seemed not to be uniform, but was observed to be along the plasmalemma where cell-to-cell contact was made. On the other hand, expression of alpha-cat or beta-cat was uneven in the trabecular-type cells which were very slender and grew in an infiltrative scattered pattern into the extracellular matrix; that was absent in the cribriform-type cells which made contact with each other mostly at the tip of the cytoplasmic processes. CONCLUSION These findings suggest that the neoplastic cells of ACC express E-cad for use in intercellular adhesion, but the cadherin-catenin complex might not operate properly, which is the cause of neoplastic cell dissociation, followed by invasion and metastasis.
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Affiliation(s)
- Y Shibuya
- Department of Oral and Maxillofacial Surgery, Kobe Steel Hospital, Kakogawa, Japan
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38
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Hugh TJ, Dillon SA, Taylor BA, Pignatelli M, Poston GJ, Kinsella AR. Cadherin-catenin expression in primary colorectal cancer: a survival analysis. Br J Cancer 1999; 80:1046-51. [PMID: 10362114 PMCID: PMC2363041 DOI: 10.1038/sj.bjc.6690461] [Citation(s) in RCA: 92] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Both cell adhesion and cell signalling events are mediated by components of the cadherin-catenin complex. Loss of expression of the components of this complex have been shown to correlate with invasive behaviour in many tumour types although their exact role in colorectal cancer remains unclear. Immunohistochemical analysis of the expression of components of the cadherin-catenin complex in colorectal cancers from 60 patients was undertaken. Loss of memberanous expression of E-cadherin, alpha-catenin and beta-catenin was demonstrated in 52%, 85% and 40% of tumours respectively. Focal nuclear expression of beta-catenin (< 75% of cells per section), usually associated with cytoplasmic expression, was clearly demonstrated in 19 (32%) tumours while widespread nuclear expression (> 75% of tumour cells per section) was seen in 11 (18%) tumours. Loss of membranous alpha-catenin expression significantly correlated with tumour de-differentiation (P = 0.009). There was a trend towards an association between advanced tumour stage and loss of membranous expression of alpha-catenin or beta-catenin, although these associations were not statistically significant. Univariate analysis revealed that advanced Dukes' stage, tumour de-differentiation, loss of membranous beta-catenin expression, cytoplasmic beta-catenin expression and widespread nuclear expression of beta-catenin all correlated with short survival following apparently curative resection of the primary tumour. However, only Dukes' stage (P = 0.002), tumour grade (P = 0.02) and widespread nuclear expression of beta-catenin (P = 0.002) were independent predictors of short survival. Disturbed growth signalling events in colorectal tumours are thought to result in nuclear accumulation of beta-catenin. Consequently, tumours with widespread nuclear expression of beta-catenin are likely to have severely abnormal growth characteristics, and which therefore might be predictive of short survival in these patients.
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Affiliation(s)
- T J Hugh
- Department of Surgery, University of Liverpool, UK
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39
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Abstract
E-cadherin and its associated cytoplasmic proteins alpha-, beta-, and gamma-catenins play important roles in cell adhesion and signal transduction, as well as in maintenance of the structural and functional organization of polarized epithelial cells. In this study, the expression, distribution, and complex assembly of catenins with E-cadherin was analysed at the steady state in a panel of human pancreatic adenocarcinoma cell lines (BxPc3, HPAF, T3M4, and PaTuII cell lines). The expression and subcellular distribution were determined by western blotting and immunocytochemistry. Co-immunoprecipitation and cross-linking studies were performed to examine the complex assembly in both Triton X-100 (TX-100)-soluble and -insoluble fractions. In BxPc3 and T3M4 cells, E-cadherin exists in two complexes, one with alpha- and gamma-catenin, and the other with beta-catenin alone. In HPAF cells there are two complexes, one consisting of E-cadherin with alpha- and beta-catenin, and another of E-cadherin with gamma-catenin. In PaTuII cells, there is only a single complex of E-cadherin with alpha-catenin and gamma-catenin. Modification of E-cadherin-catenin complexes in HPAF and PaTuII cells was associated with loss of membranous E-cadherin immunolocalization. The common denominator is impaired beta-catenin association with either E-cadherin (PaTuII) or alpha-catenin (BxPc3 and T3M4). This may suggest the presence of distinct mechanisms that modulate the assembly of each complex, which could disturb the tumour suppressor function of E-cadherin and the catenins.
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Affiliation(s)
- I El-Hariry
- Division of Investigative Science, Imperial College of Science, Technology and Medicine, Hammersmith Campus, Du Cane Road, London W12 0NN, U.K
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40
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McEntee MF, Brenneman KA. Dysregulation of beta-catenin is common in canine sporadic colorectal tumors. Vet Pathol 1999; 36:228-36. [PMID: 10332831 DOI: 10.1354/vp.36-3-228] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Human colorectal tumorigenesis is often initiated by APC (adenomatous polyposis coli) or beta-catenin (CTNNB1) mutations, which result in dysregulation of beta-catenin expression, followed by alterations in E-cadherin and/or p53. We examined 32 canine intestinal tumors for expression and intracellular distribution of beta-catenin, E-cadherin, and p53 using immunohistochemistry. beta-Catenin in normal mucosal epithelial cells was restricted to lateral cell membranes, but 13/13 (100%) colorectal adenomas had intense cytoplasmic and/or nuclear reactivity. Three of six (50%) colorectal carcinomas, 2/13 (15%) small intestinal carcinomas, and dysplastic cells in 1/2 focal hyperplastic lesions in the small intestine had a similar pattern of staining; remaining tumors had normal membranous beta-catenin reactivity. There was a correlation (P = 0.007) between abnormal beta-catenin and E-cadherin staining with 11/13 (85%) colorectal adenomas, 3/6 (50%) colorectal carcinomas, and 3/13 (23%) small intestinal carcinomas showing decreased membranous reactivity compared with normal mucosal epithelium. E-cadherin staining was reduced more often in adenomas than in carcinomas (P = 0.04). There were two patterns of nuclear p53 staining: > 60% of nuclei in 2/26 (8%) carcinomas (one colorectal, one small intestinal) were strongly labeled, whereas three colorectal adenomas and one small intestinal carcinoma had fainter staining in 10-20% of cells. Dysregulation of beta-catenin appears to be as important in canine colorectal tumorigenesis as it is in the human disease and could be due to analogous mutations. Malignant progression in canine intestinal tumors does not appear to be dependent on loss of E-cadherin or beta-catenin expression or strongly associated with overexpression of nuclear CMI antibody-reactivity p53.
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Affiliation(s)
- M F McEntee
- Department of Pathology, College of Veterinary Medicine, University of Tennessee, Knoxville
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41
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Zheng Z, Pan J, Chu B, Wong YC, Cheung AL, Tsao SW. Downregulation and abnormal expression of E-cadherin and beta-catenin in nasopharyngeal carcinoma: close association with advanced disease stage and lymph node metastasis. Hum Pathol 1999; 30:458-66. [PMID: 10208469 DOI: 10.1016/s0046-8177(99)90123-5] [Citation(s) in RCA: 100] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Nasopharyngeal carcinoma (NPC) is predominantly of the undifferentiated histological subtype. Histological differentiation is of limited prognostic significance in NPC. Recent studies have suggested that downregulation of the cadherin-catenin cell adhesion complex may play a crucial role in the initial stage of cancer invasion and metastasis and is associated with poor prognosis in human cancers. Expression of E-cadherin has not been reported previously in NPC, and its prognostic value in NPC is unknown. The purpose of this study was to examine the expression pattern of E-cadherin and its associated partner, beta-catenin, in NPC and their possible applications as prognostic markers to predict the clinical outcome of NPC. Expression of the E-cadherin and beta-catenin was examined by immunohistochemical methods in 74 cases of primary NPC and 17 of their corresponding lymph node metastases. Normal nasopharyngeal epithelium showed strong and homogeneous immunocytochemical staining of E-cadherin and beta-catenin at the cell membranes and intercellular junctions. In contrast, primary NPC showed variable and heterogeneous staining patterns of E-cadherin and beta-catenin. Loss of membranous E-cadherin expression was significantly associated with advanced stages of diseases (P<.001). Eighty percent to ninety percent of NPC in stages IV and V (Ho's staging), respectively, showed a reduced (<35%) membranous staining of E-cadherin compared with normal nasopharyngeal epithelium. Expression of beta-catenin also was downregulated in advanced NPC. Ninety percent to one hundred percent of NPC in stages IV and V (Ho's staging) expressed a reduction (<35%) of imnmunocytochemical staining of beta-catenin. The expression pattern of beta-catenin staining was strongly associated with the expression of E-cadherin (P<.001). Unlike E-cadherin, nuclear staining of beta-catenin expression was observed in some of the primary NPC and lymph node metastasis. Reduced expression of E-cadherin and beta-catenin expression was associated with a shorter survival of NPC patients (P<.001). In advanced NPC patients (stages IV and V), a significant difference in survival was observed in tumors with higher or lower levels of E-cadherin expression (P=.0224, log-rank test). These observations suggests that expression of E-cadherin and beta-catenin may have prognostic values in NPC patients.
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Affiliation(s)
- Z Zheng
- Department of Anatomy, Faculty of Medicine, University of Hong Kong, Pokfulam
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42
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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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43
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Gold JS, Reynolds AB, Rimm DL. Loss of p120ctn in human colorectal cancer predicts metastasis and poor survival. Cancer Lett 1998; 132:193-201. [PMID: 10397474 DOI: 10.1016/s0304-3835(98)00190-6] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
The p120ctn protein (formerly p120CAS) is an armadillo family member that associates directly with the cytoplasmic tail of E-cadherin and participates in the junctional complex responsible for cell-cell adhesion. Since reduced cell-cell adhesion is associated with metastasis in colorectal cancer and other neoplasms, we hypothesize that reduced expression of p120ctn may be related to metastasis in colorectal tumors. Here we describe a study of p120ctn expression in 44 primary human colorectal adenocarcinomas. As detected by immunohistochemical methods, we find altered p120ctn staining patterns in 86% of the cases. Regional complete loss of expression is seen in 18% of the cases, and it correlates with high stage disease and nodal metastasis as well as decreased survival. Although this is a preliminary study, it suggests that downregulation of p120ctn in colon cancer may be associated with metastasis and poor clinical outcome.
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Affiliation(s)
- J S Gold
- Department of Surgery, Yale University School of Medicine, New Haven, CT 06510, USA
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44
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Williams HK, Sanders DS, Jankowski JA, Landini G, Brown AM. Expression of cadherins and catenins in oral epithelial dysplasia and squamous cell carcinoma. J Oral Pathol Med 1998; 27:308-17. [PMID: 9725568 DOI: 10.1111/j.1600-0714.1998.tb01962.x] [Citation(s) in RCA: 76] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The immunocytochemical expression of cadherins and catenins was examined during the process of oral carcinogenesis by comparing their expression in normal and dysplastic epithelium with primary and metastatic carcinomas. While control epithelium showed normal distribution for P and E cadherin and the catenins, in severe dysplasia P-cadherin was upregulated. In other cases and in carcinoma-in-situ adjacent to infiltrating carcinomas, membranous expression of the cadherins and catenins was reduced or lost. The changes in expression of E-cadherin and the catenins suggest that disruption of the E-cadherin/catenin complex is a late event associated with invasion. In primary carcinomas reduced membranous and cytoplasmic staining were observed for both cadherins and catenins. Abnormal localisation of E-cadherin occurred in the more superficial parts of the better differentiated carcinomas, suggesting abnormality to the E-cadherin complex(es). In contrast, membranous expression of cadherins and catenins was reduced or lost in the deep invasive margin of primary carcinomas and in most poorly differentiated carcinomas. For E-cadherin at least, this reduction appears associated with differentiation, invasion and possibly prognosis. Possible mechanisms involved for changes in expression of the cadherins and associated catenins and areas for further study are discussed.
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Affiliation(s)
- H K Williams
- Department of Oral Pathology, School of Dentistry and Hospital, The University of Birmingham, UK
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45
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Karayiannakis AJ, Syrigos KN, Efstathiou J, Valizadeh A, Noda M, Playford RJ, Kmiot W, Pignatelli M. Expression of catenins and E-cadherin during epithelial restitution in inflammatory bowel disease. J Pathol 1998; 185:413-8. [PMID: 9828841 DOI: 10.1002/(sici)1096-9896(199808)185:4<413::aid-path125>3.0.co;2-k] [Citation(s) in RCA: 99] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Catenins are cytoplasmic proteins associated with E-cadherin, the prime mediator of cell-cell adhesion. Perturbation in any of these molecules results in altered intercellular adhesion, cell differentiation, and increased migration. In this study, the expression and cellular localization of catenins and E-cadherin in inflammatory bowel disease were examined. The expression of E-cadherin; alpha-, beta-, and gamma-catenin; and p120 was evaluated immunohistochemically in 31 paraffin-embedded colonic specimens from 21 patients with ulcerative colitis and Crohn's disease. Loss of normal membranous E-cadherin and alpha-catenin staining was detected at the mucosal edges around epithelial ulcerations in all cases of active ulcerative colitis and in 50 per cent of cases with active Crohn's disease. Reduced expression of p120 protein was also found at the margins of ulcerated mucosa in all cases of active ulcerative colitis and in 75 per cent of those with active Crohn's disease. There was a statistically significant correlation between the expression of E-cadherin, alpha-catenin and p120 and disease activity. There were no changes in beta- and gamma-catenin expression in either ulcerative colitis on Crohn's disease. These findings indicate that altered expression of E-cadherin, alpha-catenin, and p120 occurs during mucosal ulceration in inflammatory bowel disease. These changes may be involved in promoting cell migration during epithelial restitution of the gastrointestinal mucosa.
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Affiliation(s)
- A J Karayiannakis
- Department of Surgery, Imperial College of Science, Technology and Medicine, London, U.K
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46
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Raftopoulos I, Davaris P, Karatzas G, Karayannacos P, Kouraklis G. Level of alpha-catenin expression in colorectal cancer correlates with invasiveness, metastatic potential, and survival. J Surg Oncol 1998; 68:92-9. [PMID: 9624037 DOI: 10.1002/(sici)1096-9098(199806)68:2<92::aid-jso4>3.0.co;2-f] [Citation(s) in RCA: 39] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
BACKGROUND AND OBJECTIVES Decreased expression of the E-cadherin/alpha-catenin cell-cell adhesion complex is considered to elicit detachment of tumor cells from primary lesions and development of metastases. The immunohistochemical profile of alpha-catenin in colorectal cancer, as well as its correlation with differentiation, lymph node/liver metastasis and patient survival is presented in this study. METHODS Alpha-Catenin expression was investigated with immunohistochemistry technique, in 85 paraffin-embedded and 21 fresh frozen specimens, including 82 colon adenocarcinomas, 10 adenomas, 10 lymph nodes, and 3 liver metastases. Preserved alpha-catenin expression was considered for those tumors that demonstrated more than 90% alpha-catenin(+) cancer cells and reduced alpha-catenin expression for those tumors with less than 90% alpha-catenin(+) cancer cells. The chi2-test was used to calculate the statistical correlation of alpha-catenin expression with grade of differentiation and metastatic potential and the log-rank test for the correlation with survival rate. RESULTS Normal mucosa, as well as 8/10 of the colon adenomas, showed strong membranous alpha-catenin expression. Reduced alpha-catenin expression was found in 32/82 (39%) colorectal cancers examined, which was associated with de-differentiation (P < 0.01), lymph node metastasis (P < 0.025), and poor clinical outcome (P < 0.012). Alpha-Catenin expression was preserved in 3 liver metastases and their corresponding primary tumors. By contrast, 6/10 of lymphogenous metastases showed decreased alpha-catenin expression. CONCLUSIONS Our findings demonstrate a significant down-regulation of alpha-catenin expression in colorectal cancer which is associated with poor differentiation, higher metastatic potential and unfavorable prognosis. These preliminary results suggest that alpha-catenin may be a useful marker of invasiveness, metastatic potential, and survival in colorectal cancer patients.
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Affiliation(s)
- I Raftopoulos
- Second Department of Propedeutic Surgery, Laikon Hospital, Athens University Medical School, Greece
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47
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Pories SE, Hess DT, Swenson K, Lotz M, Moussa R, Steele G, Shibata D, Rieger-Christ KM, Summerhayes C. Overexpression of pp60c-src elicits invasive behavior in rat colon epithelial cells. Gastroenterology 1998; 114:1287-95. [PMID: 9609766 DOI: 10.1016/s0016-5085(98)70435-4] [Citation(s) in RCA: 22] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Src activation is reported as an early event found in preneoplastic colonic adenomas and in 70% of colon carcinomas. The aim of this study was to identify the biological consequences of c-src overexpression in rat colon epithelial cells. METHODS Introduction and overexpression of c-src in an immortalized rat colon epithelial cell line was achieved using lipofection. Transfectants were tested for changes in growth and cell behavior using different in vitro assay systems. RESULTS Colon epithelial cells overexpressing c-src showed the ability to form microcolonies in soft agar without acquiring tumorigenic potential. In in vitro assays, c-src transfectants displayed a gain of invasive potential through Matrigel without an accompanying change in migrational ability. No discernible qualitative changes were observed in the phosphotyrosyl protein profile between c-src and v-src transfectants. Assessment of the cadherin/catenin status in these cells revealed an intact, functional complex with no detectable tyrosine phosphorylation of different components of the complex. CONCLUSIONS Overexpression of c-src in an immortalized rat colon epithelial cell line does not elicit full neoplastic transformation but enhances anchorage-independent growth and confers invasion capability. Increased invasion through Matrigel was not linked to inactivation of the cadherin complex in c-src transfectants.
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Affiliation(s)
- S E Pories
- Laboratory of Cancer Biology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
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48
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Yoong KF, McNab G, Hübscher SG, Adams DH. Vascular Adhesion Protein-1 and ICAM-1 Support the Adhesion of Tumor-Infiltrating Lymphocytes to Tumor Endothelium in Human Hepatocellular Carcinoma. THE JOURNAL OF IMMUNOLOGY 1998. [DOI: 10.4049/jimmunol.160.8.3978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Abstract
T cell-mediated mechanisms are important in the defense against solid organ tumors. Why some tumors are more heavily infiltrated by T cells than others is poorly understood but is likely to depend upon adhesive interactions between circulating lymphocytes and tumor endothelium. In support of this hypothesis, the present study shows that primary human hepatocellular carcinomas (HCC) are more heavily infiltrated with T cells than colorectal hepatic metastases (CHM), and that their tumor vessels express high levels of several adhesion molecules. In HCC, an intense T cell infiltrate is observed within the tumor associated with strong expression of ICAM-1 and vascular adhesion protein-1 (VAP-1) on tumor endothelium. In contrast, fewer T cells infiltrated CHM and these tumors have little ICAM-1 and no detectable VAP-1 or VCAM-1 on tumor endothelium. T cells infiltrating both tumors are LFA-1 and very late Ag (VLA)-4 high. In vitro tissue-binding studies demonstrated that T cells bound readily to tumor endothelium in HCC, and Abs to ICAM-1, VAP-1, and to a lesser extent VCAM-1 could inhibit this binding. VAP-1 supported sialic acid-dependent adhesion under shear stress, suggesting that VAP-1 and ICAM-1 mediate, respectively, tethering and firm adhesion. In contrast, very few T cells bound to tumor vessels in CHM. Thus our data suggest that the VAP-1/VAP-1 receptor and ICAM-1/LFA-1 pathways are important in the recruitment of T cells to HCC. The strong expression of VAP-1 on tumor endothelium distinguishes HCC from CHM and supports our previous hypothesis that VAP-1 is an important hepatic endothelial adhesion molecule.
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Affiliation(s)
- Khong F. Yoong
- *Liver Research Laboratories, Queen Elizabeth Hospital, Birmingham, United Kingdom; and
| | - Gillian McNab
- *Liver Research Laboratories, Queen Elizabeth Hospital, Birmingham, United Kingdom; and
| | - Stefan G. Hübscher
- †Department of Pathology, University of Birmingham Medical School, Birmingham, United Kingdom
| | - David H. Adams
- *Liver Research Laboratories, Queen Elizabeth Hospital, Birmingham, United Kingdom; and
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Kitagawa T, Matsumoto K, Iriyama K. Serum levels of type IV collagen 7S and procollagen type III N-terminal propeptide in colorectal cancer patients with hepatic metastases. Int J Clin Oncol 1998. [DOI: 10.1007/bf02492851] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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50
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Efstathiou JA, Noda M, Rowan A, Dixon C, Chinery R, Jawhari A, Hattori T, Wright NA, Bodmer WF, Pignatelli M. Intestinal trefoil factor controls the expression of the adenomatous polyposis coli-catenin and the E-cadherin-catenin complexes in human colon carcinoma cells. Proc Natl Acad Sci U S A 1998; 95:3122-7. [PMID: 9501226 PMCID: PMC19705 DOI: 10.1073/pnas.95.6.3122] [Citation(s) in RCA: 122] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/19/1997] [Indexed: 02/06/2023] Open
Abstract
Intestinal trefoil factor 3 (TFF3) is a member of the trefoil family of peptides, small molecules constitutively expressed in epithelial tissues, including the gastrointestinal tract. TFF3 has been shown to promote migration of intestinal epithelial cells in vitro and to enhance mucosal healing and epithelial restitution in vivo. In this study, we evaluated the effect of recombinant TFF3 (rTFF3) stimulation on the expression and cellular localization of the epithelial (E)-cadherin-catenin complex, a prime mediator of Ca2+ dependent cell-cell adhesion, and the adenomatous polyposis coli (APC)-catenin complex in HT29, HCT116, and SW480 colorectal carcinoma cell lines. Stimulation by rTFF3 (10(-9) M and 10(-8) M) for 20-24 hr led to cell detachment and to a reduction in intercellular adhesion in HT29 and HCT116 cells. In both cell lines, E-cadherin expression was down-regulated. The expression of APC, alpha-catenin and beta-catenin also was decreased in HT29 cells, with a translocation of APC into the nucleus. No change in either cell adhesion or in the expression of E-cadherin, the catenins, and APC was detected in SW480 cells. In addition, TFF3 induced DNA fragmentation and morphological changes characteristic of apoptosis in HT29. Tyrphostin, a competitive inhibitor of protein tyrosine kinases, inhibited the effects of TFF3. Our results indicate that by perturbing the complexes between E-cadherin, beta-catenin, and associated proteins, TFF3 may modulate epithelial cell adhesion, migration, and survival.
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Affiliation(s)
- J A Efstathiou
- Division of Investigative Science, Imperial College of Science, Technology and Medicine, Hammersmith Campus, Du Cane Road, London W12 ONN, United Kingdom
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