Fig. 1. Working Model for Ovarian Cancer Metastasis. The initiating events in development of ovarian cancer are poorly understood. In addition to genetic mutations, the progression to neoplasia results in part from changes in the response of ovarian epithelium to mitogenic and motogenic growth factors due to aberrant expression or activity of growth factors or their receptors. Clinically, tumors often involve the ovary and omentum, with diffuse intraperitoneal metastases and malignant ascites. Reversible modulation of cell-cell and cell-matrix adhesive contacts likely plays a critical role in remodeling of the ovarian surface epithelium during tumor progression, resulting in shedding of tumor cells from the ovary and intraperitoneal metastasis, invasion and spread. Metastatic dissemination is believed to occur by direct extension or shedding of cells into the peritoneal cavity. Initial distribution of exfoliated malignant cells or multi-cellular aggregates (MCAs) is facilitated by the peritoneal fluid. Proteinase-induced changes in normal cell-cell and cell-matrix contacts play a critical role in the remodeling of ovarian epithelia that occurs during tumor progression. The ovarian tumor mileu is rich in a number of extracellular proteinases produced by the tumor cells with contributions from stromal elements including mesothelium and inflammatory cells. Following intra-peritoneal adhesion and mesothelial cell retraction, proteolytic activity is required for motility and invasion, two cellular behaviors that facilitate metastasis. Cell-matrix adhesive interactions may regulate subsequent metastatic behavior by controlling proteinase expression and trafficking. Ovarian tumors exist in an unique microenvironment wherein the primary tumor often maintains direct contact with malignant ascites, providing the opportunity for persistent exposure to soluble factors capable of modulating ovarian tumor behavior.
