Epithelial ovarian carcinoma is the leading cause of death from gynecologic malignancy, as 75% of women with this disease succumb to complications resulting from metastasis; thus, strategies aimed at prevention of metastasis would generate immediate clinical impact. Metastases are largely confined to the peritoneal cavity, indicating that microenvironmental factors that modulate intraperitoneal adhesion, motility and invasion play a predominant role in ovarian pathobiology. Acquisition of the metastatic phenotype involves disruption of cell-cell contacts and loss of extracellular matrix (ECM) constraints due to upregulation of matrix metalloproteinases (MMPs) and alterations in matrix- and mechano-transduction. While normal ovarian epithelium does not express MMPs, the transmembrane membrane type 1-MMP (MT1-MMP) is significantly elevated in borderline and malignant tumors and in peritoneal metastases. Integrin-mediated interaction of ovarian cancer cells with interstitial collagens, rich in the submesothelial ECM, represents an important early event unique to ovarian cancer metastatic dissemination. Further, our published data demonstrate that engagement of collagen binding integrins increases MT1-MMP expression and support the conclusion that matrix status influences cell surface and peri-cellular matrix degrading potential. Together these data support the hypothesis that a functional link between adhesion and proteolysis regulates ovarian cancer invasive and metastatic behavior. Experiments proposed in Aim 1 will focus on MT1-MMP surface dynamics to elucidate post-translational mechanisms that regulate surface presentation of active MT1-MMP. This will be integrated with experiments in Aim 2 to evaluate the role of matrix interactions and mechanical constraints as epigenetic factors that participate in transcriptional regulation of MT1-MMP gene expression, changes in MT1-MMP surface dynamics and acquisition of the invasive phenotype. The contribution of integrin signaling to loss of junctional E-cadherin, activation of p-catenin-mediated transcription and E- cadherin ectodomain shedding will be assesesed in Aim 3. Together these experiments will provide novel information on mechanisms by which matrix and mechanical cues in the intraperitoneal microenvironment dictate ovarian cancer metastatic potential through proteinase regulation pathways.
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