Microenvironmental Regulation of Ovarian Cancer Metastasis

Tumors arising from the ovarian surface epithelium (OSE) account for the vast majority of ovarian malignancies; however, the etiology of epithelial ovarian cancer (EOC) remains poorly understood, and the analysis of early events in ovarian carcinogenesis is limited by the relative lack of early-stage tumors for study. The normal OSE is a single layer of mesodermally derived cells that exhibit the remarkable ability to transition between epithelial and fibroblastic phenotypes in response to microenvironmental cues. Such phenotypic plasticity is usually limited to immature, regenerating, or neoplastic epithelium. Unlike most carcinomas that initially de-differentiate during neoplastic progression, ovarian carcinomas undergo a mesenchymal-epithelial transition and acquire a more differentiated epithelial phenotype resulting in significant morphologic heterogeneity as tumors acquire increasingly complex differentiation reminiscent of the highly specialized epithelia of Mullerian duct origin. Differentiated primary ovarian tumors acquire morphologic characteristics of the fallopian tube (serous carcinoma), endometrium (endometrioid carcinoma), endocervix (mucinous carcinoma), and vagina (clear cell carcinoma). More recently, classification of ovarian tumors into low-grade (type I) versus highgrade (type II) malignancies has been proposed based on presumed pathways leading to tumorigenesis, rather than histopathologic characteristics. Lowgrade carcinomas are more indolent, develop from a recognized precursor lesion, and are often confined to the ovary at diagnosis. In contrast, highgrade tumors are clinically aggressive at initial presentation, are not associated