Tumour-associated E-cadherin mutations alter cellular morphology, decrease cellular adhesion and increase cellular motility

Abstract

A major function of the cell-to-cell adhesion molecule Ecadherin is the maintenance of cell adhesion and tissue integrity. E-cadherin de®ciency in tumours leads to changes in cell morphology and motility, so that Ecadherin is considered to be a suppressor of invasion. In this study we investigated the functional consequences of three tumour-associated gene mutations that aect the extracellular portion of E-cadherin: in-frame deletions of exons 8 or 9 and a point mutation in exon 8, as they were found in human gastric carcinomas. Human MDA-MB-435S breast carcinoma cells and mouse L ®broblasts were stably transfected with the wild-type and mutant cDNAs, and the resulting changes in localization of E-cadherin, cell morphology, strength of calcium-dependent aggregation as well as cell motility and actin cytoskeleton organization were studied. We found that cells transfected with wild-type E-cadherin showed an epitheloid morphology, while all cell lines expressing mutant E-cadherin exhibited more irregular cell shapes. Cells expressing Ecadherin mutated in exon 8 showed the most scattered appearance, whereas cells with deletion of exon 9 had an intermediate state. Mutant E-cadherins were localized to the lateral regions of cell-to-cell contact sites. Additionally, both exon 8-mutated E-cadherins showed apical and perinuclear localization, and actin ®laments were drastically reduced. MDA-MB-435S cells with initial calciumdependent cell aggregation exhibited decreased aggregation and, remarkably, increased cell motility, when mutant E-cadherin was expressed. Therefore, we conclude that these E-cadherin mutations may not simply aect cell adhesion but may act in a trans-dominant-active manner, i.e. lead to increased cell motility. Our study suggests that E-cadherin mutations aecting exons 8 or 9 are the cause of multiple morphological and functional disorders and could induce the scattered morphology and the invasive behaviour of diuse type-gastric carcinomas.

Multiple ways of silencing E-cadherin gene expression in lobular carcinoma of the breast

“…When E-cadherin cDNA with in-frame deletions of exons 8 or 9, or a point mutation in exon 9, were introduced into breast cancer cell lines, the cells adopted a more malignant, invasive and aggressive behaviour relative to those cells that were transfected with wild-type cDNA. 37 Such results suggest that our findings might indicate an association between the presence of E-cadherin mutations and the invasive behaviour of the studied tumours. However, we were unable to find any association between the presence of these mutations and altered prognosis (data not shown), which was not unexpected given the relatively small numbers of tumour samples involved.…”

A protein and mRNA expression-based classification of gastric cancer

“…54 It has been suggested that mutation of exon 8 of CDH1 expresses an abnormal E-cadherin protein that lacks the appropriate signals for post-translational modifications, which permit the normal transport to the cell membrane and glycosylation of E-cadherin; this results in the arrest of E-cadherin in the Golgi apparatus. 53,55 In another report, cytoplasmic E-cadherin was present in a gastric adenocarcinoma with a 5-bp insertion in exon 9. 56 The significance of a lower aberrant p53 expression (39% vs 75%) in the two subclusters (cytoplasmic vs complete loss of E-cadherin) is unclear.…”

Genetic aberration in primary hepatocellular carcinoma: correlation between p53 gene mutation and loss-of-hetero- zygosity on chromosome 16q21-q23 and 9p21-p23

“…A major function of E-cadherin protein is the maintenance of cell adhesion and tissue integrity. E-cadherin deficiency in tumours would lead to changes in cell morphology and motility, so that E-cadherin is being considered to be a suppressor of cancer invasion [30]. In primary HCCs, E-cadherin expression is absent or reduced in amount as compared to normal liver tissues, which may be connected with intrahepatic metastasis of hepatocellular carcinoma [31], [32].…”