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PubMed · 10439038

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

G Handschuh·S Candidus·B Luber·U Reich·C Schott·S Oswald·H Becke·P Hutzler·W Birchmeier·H Höfler·K F Becker
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Abstract

A major function of the cell-to-cell adhesion molecule E-cadherin is the maintenance of cell adhesion and tissue integrity. E-cadherin deficiency in tumours leads to changes in cell morphology and motility, so that E-cadherin is considered to be a suppressor of invasion. In this study we investigated the functional consequences of three tumour-associated gene mutations that affect 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 fibroblasts 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 E-cadherin 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 filaments were drastically reduced. MDA-MB-435S cells with initial calcium-dependent 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 affect 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 affecting exons 8 or 9 are the cause of multiple morphological and functional disorders and could induce the scattered morphology and the invasive behaviour of diffuse type-gastric carcinomas.

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ActinsAnimalsCadherinsCell AdhesionCell MovementExonsFibroblastsFluorescent Antibody TechniqueHumansMammary Neoplasms, AnimalMiceMicroscopy, ConfocalModels, GeneticMutationPoint MutationStomach NeoplasmsTransfectionTumor Cells, CulturedWound HealingJournal ArticleResearch Support, Non-U.S. Gov't

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G Handschuh, S Candidus, B Luber, U Reich, C Schott, S Oswald, H Becke, P Hutzler, W Birchmeier, H Höfler, K F Becker. 1999-07-29. Tumour-associated E-cadherin mutations alter cellular morphology, decrease cellular adhesion and increase cellular motility.. https://doi.org/10.1038/sj.onc.1202790

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