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Epithelial Phenotype Confers Resistance of Ovarian Cancer Cells to Oncolytic Adenoviruses

¹ Division of Medical Genetics and Departments of ² Pathology, ³ Nephrology, and ⁴ Neurology, University of Washington; ⁵ Fred Hutchinson Cancer Research Center, Seattle, Washington; ⁶ Ruhr-University Bochum, Bochum, Germany; and ⁷ Cancer Gene Therapy Group, University of Helsinki, Helsinki, Finland

Requests for reprints: Andre Lieber, University of Washington, Box 357720, Seattle, WA 98195. Phone: 206-221-3973; Fax: 206-685-8675; E-mail: lieber00{at}u.washington.edu.

Key Words: adenovirus • cancer gene therapy • ovarian cancer

We studied the susceptibility of primary ovarian cancer cells to oncolytic adenoviruses. Using gene expression profiling of cancer cells either resistant or susceptible to viral oncolysis, we discovered that the epithelial phenotype of ovarian cancer represents a barrier to infection by commonly used oncolytic adenoviruses targeted to coxsackie-adenovirus receptor or CD46. Specifically, we found that these adenovirus receptors were trapped in tight junctions and not accessible for virus binding. Accessibility to viral receptors was critically linked to depolarization and the loss of tight and adherens junctions, both hallmarks of epithelial-to-mesenchymal transition (EMT). We showed that specific, thus far little-explored adenovirus serotypes (Ad3, Ad7, Ad11, and Ad14) that use receptor(s) other than coxsackie-adenovirus receptor and CD46 were able to trigger EMT in epithelial ovarian cancer cells and cause efficient oncolysis. Our studies on ovarian cancer cultures and xenografts also revealed several interesting cancer cell biology features. Tumors in situ as well as tumor xenografts in mice mostly contained epithelial cells and cells that were in a hybrid stage where they expressed both epithelial and mesenchymal markers (epithelial/mesenchymal cells). These epithelial/mesenchymal cells are the only xenograft-derived cells that can be cultured and with passaging undergo EMT and differentiate into mesenchymal cells. Our study provides a venue for improved virotherapy of cancer as well as new insights into cancer cell biology. [Cancer Res 2009;69(12):5115–25]