Growth and apoptosis in surface epithelial ovarian cancer

grantor: University of TorontoOvarian cancer is the leading cause of death from gynecologic malignancy. 80-90% of ovarian cancers in the adult originate from the ovarian surface epithelium (OSE). We hypothesize that the majority of ovarian cancers originate from OSE lined inclusion cysts which fail to be eliminated in the stroma. To identify the naturally occurring ligands that are involved in activating the mechanisms by which inclusion cysts are normally eliminated, we examined the ability of anti-Fas mAb, known to activate the Fas receptor, to induce apoptosis in two cell lines, HEY and Caov-3, derived from ovarian carcinomas of surface epithelial origin. Treatment of each cell line with anti-Fas mAb caused chromatin condensation, nuclear segmentation and apoptotic body formation, morphological changes indicative of apoptosis. Furthermore, we have shown that anti-Fas mAb activates the sphingomyelin-ceramide signal transduction pathway. Treatment of Caov-3 cells for 30 min caused a 40% decrease in the total sphingomyelin content. The six most abundant sphingomyelin species identified in Caov-3 cells were 34:1, 36:1, 40:1, 41:1, 42:1, and 42:2. Specifically three of these species, 34:1, 40:1 and 42:2, were significantly reduced upon treatment with anti-Fas mAb. Treatment of these cell lines with ceramide, a product of sphingomyelin hydrolysis, using a cell permeable analogue C$\sb2$-ceramide, also caused the above cells to undergo apoptosis. The ability of anti-Fas mAb and C$\sb2$-ceramide to induce apoptosis was also observed in ovarian cancer cells derived from ascites fluid of a patient with ovarian cancer. Therefore, the Fas ligand/receptor system acting through the sphingomyelin-ceramide pathway, provides a mechanism by which ovarian surface epithelial cancer cells can be induced to undergo apoptosis. Thus, the lack of proper functioning of this apoptotic mechanism can lead to ovarian tumorigenesis. (Abstract shortened by UMI.)M.Sc