Metastatic dissemination of human ovarian epithelial carcinoma is promotedby alpha 2 beta 1-integrin-mediated interaction with type I collagen

Metastatic dissemination of epithelial ovarian carcinoma is thought to be m ediated via tumor cell exfoliation into the peritoneal cavity, followed by adhesion to and invasion through the mesothelium which overlies the content s of the peritoneal cavity. In this study, we have utilized short-term prim ary cultures to analyze the effect of specific extracellular matrix protein s on properties of human ovarian epithelial carcinoma cells which contribut e to the invasive phenotype. Analysis of cell:matrix adhesive profiles indi cated that ovarian carcinoma cells adhere preferentially to type I collagen . Immunoprecipitation analyses demonstrated the presence of the collagen-bi nding alpha 2 beta 1 integrin in biotin-labeled ovarian carcinoma cell memb ranes, and cellular adhesion was inhibited by blocking antibodies directed against the alpha 2 and beta 1 integrin subunits. The alpha 2 beta 1-bindin g peptide Asp-Gly-Glu-Ala (DGEA) was also moderately effective at blocking adhesion to collagen relative to the control peptide Ala-Gly-Glu-Ala (AGEA) . Analysis of cell motility on protein-coated colloidal gold coverslips dem onstrated that ovarian carcinoma cells migrate preferentially on type I col lagen coated surfaces. Type I collagen promoted migration in a concentratio n-dependent, saturable manner, with maximal migration observed at a collage n-coating concentration of 50 mu g/ml. Migration on collagen was inhibited by antibodies directed against the alpha 2 and beta 1 integrin subunits and by DGEA peptide, providing evidence for the role of the alpha 2 beta 1 int egrin in ovarian carcinoma cell motility. Culturing ovarian carcinoma cells on type I collagen gels led to a significant increase in conversion of the matrix metalloproteinase 2 zymogen to the 66-kD form, suggesting that adhe sion to collagen also influences matrix-degrading proteinases. These data s uggest that alpha 2 beta 1-integrin-mediated interaction of ovarian carcino ma cells with type I collagen, a protein prevalent both in the mesothelial extracellular matrix and in the peritoneal cavity of ovarian carcinoma pati ents, may function on multiple levels to promote metastatic dissemination o f ovarian carcinoma cells.