STEROIDOGENESIS-INDUCING PROTEIN, ISOLATED FROM HUMAN OVARIAN FOLLICULAR-FLUID, IS A POTENT MITOGEN FOR CELL-LINES DERIVED FROM OVARIAN SURFACE EPITHELIAL CARCINOMAS

The majority of human ovarian cancers originate from the surface epith elial (OSE) cells that surround the ovary. The incidence of OSE cancer is correlated with the number of ovulations that occur during fertile life. OSE cells remain quiescent but undergo rapid mitotic activity a fter ovulation to repair the wound. This increase in mitotic activity following each ovulation may give rise to mutations that make the OSE susceptible to malignant transformation. Steroidogenesis-inducing prot ein (SIP), a protein isolated from human follicular fluid obtained fro m hyperstimulated ovaries, is a potent mitogen for several gonadal cel ls, To investigate the possibility that SIP may be involved in the pro liferation of OSE cells, we have studied its effects on DNA synthesis in seven cell lines derived from OSE carcinomas (HEY, MLS, SKA, OW-1, SAU, NIH:OVCAR-3, and Caov-3), The cells were cultured in serum-free m edium in the presence of SIP for 18 hr, followed by incubation with [H -3]thymidine for 4 hr. The radioactivity incorporated into the DNA was measured, SIP stimulated DNA synthesis in six of the cell lines. HEY, SKA, MLS, and OVCAR3 were most responsive to SIP. Interactions betwee n SIP and other growth factors and cytokines known to be present in fo llicular fluid (EGF/TGF alpha, TGF beta, FGF, IGF-1, IL-1 beta, and TN F alpha) were also investigated in HEY and SKA cells. EGF/TGF alpha an d IGF-1 potentiated the effects of SIP. TGF beta had no effect on SIP, and/or EGF/TGF alpha stimulated DNA synthesis, Other growth factors w hich were tested in this study had no effect on DNA synthesis in SKA c ells. Dibutyryl cyclic-AMP blocked the effects of SIP on DNA synthesis . We conclude that SIP is a potent mitogen for OSE cell lines and toge ther with TGF alpha and IGF-1 may be involved in the proliferation of normal OSE cells after ovulation. Since SIP is obtained from the preov ulatory follicle, itmay represent a link between the number of ovulati ons and the increased incidence of OSE cancers. (C) 1997 Academic Pres s.