Human ovarian surface epithelium and ovarian cancer. Aspects of growth regulation

Abstract

The ovary is covered with a single layer of epithelial cells, the ovarian surface epithelium (OSE). The OSE is degraded during every menstrual cycle to enable ovulation, and is subsequently reconstituted to cover the rupture site. This single cell layer is proposed as the origin for about 90 % of all ovarian cancers. The active proliferative phases of the OSE after each ovulation is proposed to be the cause for its frequent transformation, since intensive cell growth enhances the risk for accumulation of mutations. The exposure of the OSE to high gonadotropin levels in postmenopausal women has also been suggested as an underlying factor, since the incidence of ovarian cancers increase during the postmenopausal period. Ovarian cancer has also been suggested to be a cytokine-propelled disease, since the ovarian cancer cells often both secrete cytokines, express cytokine receptors, and are growth stimulated by cytokines.In this study, the levels of the chemotactic cytokine interleukin-8 (IL-8) was found to be about 13 times higher in cyst fluids from malignant ovarian tumors compared to cyst fluids from benign tumors or simple cysts. The IL-8 levels in plasma samples did not differ between patients with benign and malignant ovarian tumors, and thus this factor may be of limited clinical importance as an ovarian cancer marker. IL-8 was found to be expressed in both epithelial tumor cells and stromal cells within the tumors, and the tissue levels of IL-8 increased with the malignancy of the tumors. The presence of both types of IL-8 receptors on ovarian cancer cells indicated a direct role for IL-8 on the tumor cells. In cultures of both normal human OSE cells and ovarian cancer cells, IL-8 was secreted into the media, and addition of a neutralizing antibody against IL-8, eliminating the autocrine stimulation, decreased the cell growth. These results demonstrate a possible tumor-promoting role for IL-8 in ovarian carcinomas.The expression of IL-8 is partly regulated by the transcription factor C/EBPb. This growth activating factor was also increased in the more malignant ovarian cancers, while the closely related antimitotic factor C/EBPa was constantly expressed in the different tumors, and its cytoplasmic location indicated a passive role for this factor.OSE cells in culture was not found to be growth stimulated by either of the gonadotropins follicle-stimulating hormone (FSH) or luteinizing hormone (LH), a result that argues against gonadotropin-induced proliferation as a factor in ovarian cancer development. OSE cells was demonstrated to produce both estradiol and progesterone in vitro, showing that steroid production from ovarian cancers is not a property acquired through transformation but a normal feature of OSE cells. Estradiol did not influence the growth rate of OSE cells in vitro, while the addition of a progesterone receptor blocker, Org 31710, increased the growth rate in OSE cells from postmenopausal cells. This indicates a growth inhibiting role of progesterone, which would be in line with epidemiological studies reporting a protective effect against ovarian cancer connected with the use of oral contraceptives and pregnancies, where progesterone levels are high.