Sequential Molecular and Cellular Events during Neoplastic Progression: A Mouse Syngeneic Ovarian Cancer Model

Abstract

Studies performed to identify early events of ovarian cancer and to establish molecular markers to support early detection and development of chemopreventive regimens have been hindered by a lack of adequate cell models. Taking advantage of the spontaneous transformation of mouse ovarian surface epithelial (MDSE) cells in culture, we isolated and characterized distinct transitional stages of ovarian cancer as the cells progressed from a premalignant nontumorigenic phenotype to a highly aggressive malignant phenotype. Transitional stages were concurrent with progressive increases in proliferation, anchorage-independent growth capacity, in vivo tumor formation, and aneuploidy. During neoplastic progression, our ovarian cancer model underwent distinct remodeling of the actin cytoskeleton and focal adhesion complexes, concomitant with downregulation and/or aberrant subcellular localization of two tumor-suppressor proteins Ecadherin and connexin-43. In addition, we demonstrate that epigenetic silencing of E-cadherin through promoter methylation is associated with neoplastic progression of our ovarian cancer model. These results establish critical interactions between cellular cytoskeletal remodeling and epigenetic silencing events in the progression of ovarian cancer. Thus, our MDSE model provides an excellent tool to identify both cellularand molecular changes in the early and late stages of ovarian cancer, to evaluate their regulation, and to determine their significance in an immunocompetent in vivo environment.