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[Cancer Research 63, 2172-2178, May 1, 2003]
© 2003 American Association for Cancer Research

Molecular Biology and Genetics

The Protein Kinase Akt Induces Epithelial Mesenchymal Transition and Promotes Enhanced Motility and Invasiveness of Squamous Cell Carcinoma Lines1

Sylvia Julien Grille2, Alfonso Bellacosa2,3, John Upson, Andres J. Klein-Szanto, Frans van Roy, Whaseon Lee-Kwon, Mark Donowitz, Philip N. Tsichlis and Lionel Larue4

Developmental Genetics of Melanocytes, UMR 146 CNRS-Institut Curie, 91405 Orsay Cedex, France [S. J. G., L. L.]; Human Genetics Program [A. B., J. U.] and Department of Pathology [A. J. K-S.], Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111; Department for Molecular Biomedical Research, VIB-Ghent University, B-9000 Ghent, Belgium [F. v. R.]; Hopkins Center for Epithelial Disorders, Johns Hopkins School of Medicine, Baltimore, Maryland 21205 [W. L-K., M. D.]; and Molecular Oncology Research Institute, Tufts-New England Medical Center, Boston, Massachusetts 02111 [P. N. T.]

Epithelial-mesenchymal transition (EMT) is an important process during development and oncogenesis by which epithelial cells acquire fibroblast-like properties and show reduced intercellular adhesion and increased motility. Squamous cell carcinoma lines engineered to express constitutively active Akt underwent EMT, characterized by down-regulation of the epithelial markers desmoplakin, E-cadherin, and ß-catenin and up-regulation of the mesenchymal marker vimentin. The cells lost epithelial cell morphology and acquired fibroblast-like properties. Additionally, E-cadherin was down-regulated transcriptionally. The cells expressing constitutively active Akt exhibited reduced cell-cell adhesion, increased motility on fibronectin-coated surfaces, and increased invasiveness in animals. AKT is activated in many human carcinomas, and the AKT-driven EMT may confer the motility required for tissue invasion and metastasis. These findings suggest that future therapies based on AKT inhibition may complement conventional treatments by controlling tumor cell invasion and metastasis.




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