Microenvironment regulation of proteinase expression and E-cadherin ectodomain generation in ovarian cancer

Most women diagnosed with epithelial ovarian carcinoma (EOC) initially present with metastases, but little is known about the regulation of ovarian tumor cell dissemination by the tumor microenvironment. Because ovarian cancer cell dissemination is mostly limited to the peritoneal cavity and often results in the accumulation of malignant ascites, the ovarian tumor microenvironment is unique in comparison to other cancers. The ascites maintains constant contact with the primary tumor and peritoneal metastases and contains many factors that foster metastatic spread. Reversible modulation of cell-cell adhesion, cell-matrix adhesion, and proteolytic activity also play a critical role in remodeling of the neoplastic ovarian epithelium, subjecting these processes to microenvironment regulation and implicating collagen-binding integrins and lysophosphatidic acid (LPA) in both E-cadherin and proteinase regulation.; The studies presented in this dissertation now identify and dissect several tumor microenvironment-regulated mechanisms that influence E-cadherin function and proteinase expression to potentially increase the metastatic propensity of ovarian cancer. In contrast to most carcinomas that lose E-cadherin expression with progression, E-cadherin expression is gained during ovarian cancer progression. Mutations in the E-cadherin gene are rare, but other mechanisms likely affect E-cadherin expression and/or function to enhance metastasis. Here, collagen-binding integrin engagement has been shown to regulate two distinct observations involving E-cadherin function. First, integrin engagement increases E-cadherin internalization and GSK-3beta inhibition, resulting in increased beta-catenin-mediated transcription and protein expression of known Wnt/beta-catenin targets associated with ovarian cancer metastasis (uPA, COX-2, MT1-MMP, MMP-7). Second, integrin engagement enhances MMP-9-dependent E-cadherin cleavage and ectodomain (sE-cad) shedding. sE-cad levels are elevated in EOC patient ascites and incubation of EOC cells with physiologically relevant concentrations of recombinant sE-cad disrupts cell-cell junctions. LPA also promotes the development of a more aggressive phenotype in EOC cells via different mechanisms. MMP-9-dependent E-cadherin ectodomain shedding is increased following LPA treatment and LPA also increases COX-2 expression in EOC cells. COX-2 then functions as a downstream mediator of LPA to increase pro-MMP-2 activation, cell migration, and invasion. Together, these novel results further elucidate mechanisms that may govern ovarian cancer metastasis and identify potential therapy targets for thousands of ovarian cancer patients.