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The Role of the Microenvironment in Early Ovarian Cancer Metastasis

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One of the most important characteristics of ovarian cancer (OvCa) is metastasis of cancer cells to the peritoneal cavity. The main site of OvCa metastasis is the omentum. The omental microenvironment is composed of a layer of mesothelial cells covering the underlying stroma composed of extra-cellular matrices (ECMs) and stromal cells (i.e. fibroblasts and adipocytes). Adipocytes are the main cell type (over 80%) present in omentum . OvCa metastasis requires the initial adhesion and invasion of cancer cells into the surface of the omentum. Our preliminary results show that a number of factors in the microenvironment regulate the initial steps of OvCa metastasis to the omentum including stromal cells (i.e. mesothelial cells, fibroblasts, adipocytes), different extra-cellular matrices (ECMs) (i.e. fibronectin), adhesion molecules (i.e. a51-integrin), and proteases (i.e. matrix-metalloproteinase 2 [MMP-2]). However, the mechanisms involved in early OvCa cell metastasis have yet to be fully elucidated. The objectives of this project during the mentored phase are to determine the functional significance of MMP-2, to differentiate the functional roles of FN and its receptor, a51-integrin, and to clarify the functional value of adipocytes as conductors of early OvCa metastasis. During the independent phase of the award, the intent is to discover new inhibitors of OvCa cell adhesion and metastasis and to further investigate and evaluate the functional significance of adipocytes as regulators of early OvCa metastasis. Our overall hypothesis is that the OvCa microenvironment plays a critical role in OvCa adhesion and invasion as the first step of metastasis.

Most patients with OvCa present in an advanced stage that involves the dissemination of cancer cells throughout the peritoneum cavity. Even after aggressive surgical debulking, tumors repopulate the abdominal cavity, and treatment is hampered by a lack of understanding of OvCa metastasis. This proposal will investigate adhesion and invasion, the initial rate-limiting steps of early OvCa metastasis. To design new and effective treatments, it is important that we understand the mechanisms of OvCa cell adhesion to the omentum, prior to establishment of single metastases. In pursuit of this goal, we have designed a three dimensional model of the surface of the omentum using primary human mesothelial cells and fibroblasts with ECM. This model gives us the opportunity to study in vitro the distinct roles of each cellular and ECM component present in the OvCa microenvironment on metastasis.

RELEVANCE: The potential long-term clinical application of our studies is to identify early intraperitoneal treatment that inhibits OvCa cell (primary tumor or ascites-derived) adhesion (i.e. MMP-2 selective inhibitor) to the peritoneal cavity and metastasis. The OvCa patients that will benefit from early treatment include patients with advanced disease who, at the end of surgery, were rendered macroscopically tumor free (approximately 70% of FIGO stage IIIB to IV) and have only presumed "microscopic disease", and patients with ascites whose disease is limited to the ovary (FIGO stage IC to IIIA).

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