Role of adhesion and proteolysis in epithelial ovarian carcinoma dissemination
Metastatic spread of epithelial ovarian carcinoma (OV CA) is mediated primarily by surface shedding of tumor cells and peritoneal implantation; however the role of adhesion and proteolysis in OV CA remains unclear. We have previously shown that OV CA cells have enhanced proteolytic capacity relative to normal ovarian epithelium. Furthermore, previous data has demonstrated that plasminogen activation is regulated post-translationally by interaction with the extracellular matrix (ECM), suggesting a mechanism by which the extracellular environment may modulate the activity of tumorassociated proteinases. To analyze the role of adhesion and proteolysis in ovarian cancer dissemination, we have characterized immortalized cell lines and primary cultures of of OV CA with respect to adhesive properties and proteinase production. Contrary to most tumor cells, OV CA exhibited preferential adhesion to type I collagen (CI). Analysis of adhesion molecule expression by cell surface ELISA, immunoprecipitation and immunohistochemistry confirmed the presence of the CI binding alpha2betal (a2bl ) integrin. Anti-a2 or bl subunit antibodies blocked adhesion by 60-95%. To determine whether the adhesive substratum altered proteinase production, cells grown on a variety of ECM protein substrata were assayed for proteinase activity. A 40-70% increase in u-PA activity was observed in cells grown on CI or an intact CI-rich 3-dimensional ECM. As the OV CA microenvironment in vivo is rich in CI, these data suggest that preferential adhesion to CI followed by enhanced u-PA secretion may represent a biochemical mechanism by which the inlraperitoneal dissemination of OV CA is mediated.
Stack, MS; Moser, TL; Bafetti, LM; Pizzo, SV; Fishman, DA
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