A causal role for E-cadherin in the transition from adenoma to carcinoma

Perl, Anne‐Karina T.; Wilgenbus, Petra; Dahl, Ulf; Semb, Henrik; Christofori, Gerhard

doi:10.1038/32433

Cited by 1,272 publications

(980 citation statements)

References 22 publications

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“…6,8,38 Most importantly, a causal role for E-cadherin in the transition from adenoma to carcinoma of the pancreas was shown using transgenic mouse models. 39 In many human cancers, a positive correlation was also frequently noted between a decreased expression of E-cadherin and tumor aggressiveness. 9,40 -42 However, it is noteworthy that we could not find any difference in the expression of E-cadherin at the mRNA and protein levels between the 2 types of HT-29 cells.…”

Section: Immunofluorescence Analysis Of the Distribution Of E-cadherimentioning

confidence: 99%

Requirement of both mucins and proteoglycans in cell‐cell dissociation and invasiveness of colon carcinoma HT‐29 cells

Truant

Bruyneel

Gouyer

et al. 2003

Intl Journal of Cancer

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Key words: colon carcinoma cells; E-cadherin; mucins; heparan sulfate proteoglycansEpithelial E-cadherin, a component of the adherens junctions, is crucial for the organization and maintenance of differentiated epithelia. 1 The extracellular NH2-terminal domain of this transmembrane glycoprotein mediates cell-cell adhesion in a homophilic and Ca 2ϩ -dependent way. The COOH-terminal domain binds to the actin cytoskeleton via ␣-catenin and ␤-catenin or plakoglobin. 2 Studies in cancer cell lines have shown that changes in the structure or in the expression of the components of the E-cadherin/␤-catenin complex result in the suppression of cell-cell adhesion and in the expression of an invasive phenotype. [3][4][5][6][7][8] In cancer, the maintenance of the epithelia is lost and dissociation of cells is associated with metastatic dissemination. This phenomenon can occur through a decrease in the expression level of E-cadherin and, regarding colon cancer, such decrease has been related to the tumor grade and clinical outcome. 9 At the genomic level, loss of E-cadherin expression does not occur as a result of mutation of E-cadherin gene, whereas mutations of ␤-catenin were found in a small proportion of colon cancers. 10 -12 In another way, E-cadherin-mediated cell-cell adhesion may be modulated by the mucin-like glycoprotein MUC1, which is often overexpressed in cancer. MUC1, also termed episialin, is a membrane-associated glycoprotein composed of a membrane anchor and a mucin-like ectodomain. 13 In human ZR-75-1 breast cancer cells, the cytoplasmic domain of MUC1 was shown to bind ␤-catenin, leading to a decrease of E-cadherin-catenin complex and an anti-adhesion effect. 14 On the other hand, MUC1 was shown to cause steric hindrance of adhesion molecules like E-cadherin, through its large negatively charged extracellular domain, which contains many oligosaccharide side chains. 15,16 Proteoglycans were also shown to disturb the function of E-cadherin through steric hindrance in variants of the murine mammary gland cell line NMuMG and the canine epithelial kidney cell line MDCK. 17 During colorectal carcinogenesis, the expression of MUC1 was found upregulated, particularly in later stages of the disease. 18 -20 On the other hand, de novo appearance of a secreted mucin normally found in the stomach, MUC5AC, has been described in colon carcinomas. [21][22][23] Thus, mucinous differentiated cells are present in colorectal carcinomas and more particularly in mucinous carcinomas and in signet ring cell carcinomas. Until now, the significance of a differentiation characteristic into a mucin-secreting phenotype with regard to the tumor development is still unknown.To investigate the role of mucins in the invasive properties of colon carcinoma cells, the HT-29 cell line is an appropriate model, as the cells of this cell line express different phenotypes: besides a majority of undifferentiated cells (Ͼ95%), a small proportion of cells presents a capacity to differentiate into a mucinous phenotype or into an enterocyte-like ...

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Section: Immunofluorescence Analysis Of the Distribution Of E-cadherimentioning

confidence: 99%

Requirement of both mucins and proteoglycans in cell‐cell dissociation and invasiveness of colon carcinoma HT‐29 cells

Truant

Bruyneel

Gouyer

et al. 2003

Intl Journal of Cancer

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“…Downregulation of cadherins or their functional alterations have been frequently observed in human malignancies, which promotes tumor cell invasion and metastasis (Berx et al, 1995;Perl et al, 1998), suggesting that at least some cadherins can act as tumor suppressor genes (TSG). Mutations of E-cadherin (CDH1) have been reported in familial and sporadic gastric cancers and other tumors (Risinger et al, 1994;Berx et al, 1995;Guilford et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Functional epigenetics identifies a protocadherin PCDH10 as a candidate tumor suppressor for nasopharyngeal, esophageal and multiple other carcinomas with frequent methylation

Ying

Seng³

et al. 2005

Oncogene

245

288

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Protocadherins constitute the largest subgroup in the cadherin superfamily of cell adhesion molecules. Their major functions are poorly understood, although some are implicated in nervous system development. As tumorspecific promoter methylation is a marker for tumor suppressor genes (TSG), we searched for epigenetically inactivated TSGs using methylation-subtraction combined with pharmacologic demethylation, and identified the PCDH10 CpG island as a methylated sequence in nasopharyngeal carcinoma (NPC). PCDH10 is broadly expressed in all normal adult and fetal tissues including the epithelia, though at different levels. It resides at 4q28.3 -a region with hemizygous deletion detected by array-CGH in NPC cell lines; however, PCDH10 itself is not located within the deletion. In contrast, its transcriptional silencing and promoter methylation were frequently detected in multiple carcinoma cell lines in a biallelic way, including 12/12 nasopharyngeal, 13/16 esophageal, 3/4 breast, 5/5 colorectal, 3/4 cervical, 2/5 lung and 2/8 hepatocellular carcinoma cell lines, but not in any immortalized normal epithelial cell line. Aberrant methylation was further frequently detected in multiple primary carcinomas (82% in NPC, 42-51% for other carcinomas), but not normal tissues. The transcriptional silencing of PCDH10 could be reversed by pharmacologic demethylation with 5-aza-2 0 -deoxycytidine or genetic demethylation with double knockout of DNMT1 and DNMT3B, indicating a direct epigenetic mechanism. Ectopic expression of PCDH10 strongly suppressed tumor cell growth, migration, invasion and colony formation. Although the epigenetic and genetic disruptions of several classical cadherins as TSGs have been well documented in tumors, this is the first report that a widely expressed protocadherin can also function as a TSG that is frequently inactivated epigenetically in multiple carcinomas.

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“…The Ecadherin/catenin complexes represent the main adhesion system responsible for the maintenance of cell-cell contacts in epithelial tissues (Takeichi, 1995;Huber et al, 1996). Downregulation of E-cadherin expression or functional perturbations of the E-cadherin/catenin complexes frequently occur during the progression of carcinomas (Takeichi, 1993;Birchmeier and Behrens, 1994;Christofori and Semb, 1999), and has been casually linked to the progression of adenoma to invasive carcinoma (Perl et al, 1998). The molecular bases of E-cadherin downregulation during tumour progression have started to be elucidated in the last years.…”

Section: Introductionmentioning

confidence: 99%

Snail silencing effectively suppresses tumour growth and invasiveness

et al. 2006

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The transcription factor Snail has been recently proposed as an important mediator of tumour invasion because of its role in downregulation of E-cadherin and induction of epithelial-mesenchymal transitions (EMT). This behaviour has led to the consideration of Snail as a potential therapeutic target to block tumour progression. In this report, we provide evidence for this hypothesis. We show that silencing of Snail by stable RNA interference in MDCK-Snail cells induces a complete mesenchymal to epithelial transition (MET), associated to the upregulation of E-cadherin, downregulation of mesenchymal markers and inhibition of invasion. More importantly, stable interference of endogenous Snail in two independent carcinoma cell lines leads to a dramatic reduction of in vivo tumour growth, accompanied by increased tumour differentiation and a significant decrease in the expression of MMP-9 and angiogenic markers and invasiveness. These results indicate that use of RNA interference can be an effective tool for blocking Snail function, opening the way for its application in new antiinvasive therapies.

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A causal role for E-cadherin in the transition from adenoma to carcinoma

Cited by 1,272 publications

References 22 publications

Requirement of both mucins and proteoglycans in cell‐cell dissociation and invasiveness of colon carcinoma HT‐29 cells

Requirement of both mucins and proteoglycans in cell‐cell dissociation and invasiveness of colon carcinoma HT‐29 cells

Functional epigenetics identifies a protocadherin PCDH10 as a candidate tumor suppressor for nasopharyngeal, esophageal and multiple other carcinomas with frequent methylation

Snail silencing effectively suppresses tumour growth and invasiveness

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