BINDING OF OVARIAN-CANCER CELLS TO PERITONEAL MESOTHELIUM IN-VITRO ISPARTLY MEDIATED BY CD44H

Epithelial cancer of the ovary spreads by implantation of tumor cells onto the mesothelial lining of the peritoneal cavity. We have develope d an in vitro binding assay using confluent monolayers of normal perit oneal mesothelial cells in order to assess the role of known adhesion proteins in this process. Cells from normal ovarian surface epithelium , and the ovarian cancer cell lines CAOV-3 and SKOV-3 exhibited signif icant adhesion to mesothelium in vitro (range 33-56% specific binding) . Although these cells expressed several adhesion molecules, including CD44 and integrins such as alpha4beta1, alpha5beta1, and alphanubeta3 , only anti-CD44 antibody was capable of inhibiting mesothelial bindin g (range 42-44% inhibition). Adhesion molecule expression was also det ermined for fresh ovarian specimens, with CD44 being expressed in 2 of 2 cases of normal ovarian epithelium, 15 of 16 (94%) cases of tissue- derived tumor (from primary sites or peritoneal implants), and only 2 of 8 (25%) cases of free-floating tumor cells from ascites. Three of t hree CD44-positive cases derived from peritoneal implants exhibited si gnificant mesothelial binding which was partly blocked by anti-CD44 an tibody, whereas 2 of 2 CD44-negative cases derived from ascites showed minimal binding. CD44-mediated binding of ovarian cancer cells was de termined to be due to recognition of mesothelium-associated hyaluronat e, suggesting that the CD44H isoform was involved in this process. Imm unoprecipitation of the CD44 species expressed by ovarian cancer cells revealed 2 major bands at 85-90 and 180 kDa, consistent with the know n molecular masses of CD44H. These results suggest that CD44H may be a n important mediator of ovarian cancer cell implantation and that decr eased CD44H expression may be associated with release of cells into th e peritoneal space during ascites formation. It is possible that strat egies to interfere with CD44H function may result in decreased intraab dominal spread of this highly lethal neoplasm.