Model System to Investigate the Effect of BRCA1 and/or p53 Inactivation in the Ovarian Stroma on Growth and Transformation Potential of the Ovarian Epithelium

摘要

Women carrying germline mutations in BRCA1 are at high risk for developing ovarian cancer and mutations in p53 are frequently detected in ovarian tumors. The tumor microenvironment plays an important role in cancer progression. The tumor stroma promotes angiogenesis and is a source of growth factors, chemokines, and extracellular matrix (ECM) molecules that promotes carcinoma progression. We investigated the effects of loss of function of BRCA1 or BRCA1 and Trp53 in the stroma on the growth and neoplastic transformation of epithelial cells using 2D and 3D in vitro cell culture models. A growing number of studies suggest that selective inactivation of BRCA1 or p53 in the stroma surrounding tumors plays a direct role in tumor progression. Therefore, to directly test the hypothesis that stromal cells exert cell-nonautonomous effects on ovarian epithelial cell growth and neoplastic transformation, we examined the effects of culturing mouse ovarian surface epithelial (MOSE) cells with ECM and conditioned media from stromal cells in which BRCA1 or BRCA1 and Trp53 were inactivated.