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

Oncogene volume 18, pages 4301–4312 (1999)Cite this article

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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Acknowledgements

We are grateful to Drs M Takeichi and N Nagafuchi (Department of Biophysics, Faculty of Science, Kyoto University, Kyoto, Japan) for the transfection plasmid pBATEM. We thank Drs J Behrens, J Huelsken and S Meiners (Max Delbrück Centrum, Berlin, Germany) for technical advice and J Huelsken for the Neuro 2A neuroblastoma cells and the vector pSV2neo. We thank Drs A Luz, M Atkinson (Institut für Pathologie, GSF, Neuherberg, Germany) and G Keller (Institut für Pathologie, TU-München, Munich, Germany) for helpful discussions, and E Mannweiler (Institut für Pathologie, GSF, Neuherberg, Germany) and E Mentele for excellent technical assistance. The authors are thankful to Dr J Mueller (Institut für Chirurgie, TU-München, München, Germany) for critical reading of the manuscript. This work was supported by a Grant to Dr K-F Becker (Be1501) from the Deutsche Forschungsgemeinschaft (DFG).

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  1. Gabriele Handschuh and Sonja Candidus: G Handschuh and S Candidus contributed equally to this study

Authors and Affiliations

  1. GSF-Forschungszentrum für Umwelt and Gesundheit, Institut für Pathologie, Neuherberg, D-85764, Germany

    Gabriele Handschuh, Birgit Luber, Ulrike Reich, Sandra Oswald, Helma Becke, Peter Hutzler, Heinz Höfler & Karl-Friedrich Becker

  2. Technische Universität München, Klinikum rechts der Isar, Institut für Pathologie, München, D-81675, Germany

    Sonja Candidus, Christina Schott, Heinz Höfler & Karl-Friedrich Becker

  3. Max-Delbrück-Center für Molekulare Medizin, Berlin, D-13122, Germany

    Walter Birchmeier

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Handschuh, G., Candidus, S., Luber, B. et al. Tumour-associated E-cadherin mutations alter cellular morphology, decrease cellular adhesion and increase cellular motility. Oncogene 18, 4301–4312 (1999). https://doi.org/10.1038/sj.onc.1202790

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