Induction of Proliferation in the Primate Ovarian Surface Epithelium In Vivo

Abstract

Epithelial ovarian cancer (EOC), the most lethal gynecologic malignancy in women, has resisted direct testing of possible causes in part because, among other mammals, only primates are affected. Proliferation has been proposed as a mode of transformation of the ovarian surface epithelium (OSE). This study examined OSE proliferation in the rhesus macaque, a monkey whose reproductive physiology resembles that of humans. In particular, the question was addressed of whether primate OSE can undergo proliferative repair in vivo in a manner that might relate to the cause of EOC. Macaque ovaries were collected at 3 stages of the menstrual cycle. Very late luteal-phase ovaries were gently brushed during laparoscopy to remove part of the OSE, and groups of ovaries numbering 3 or less were collected after 1 to 4 days. Ovaries also were sampled from 10 women ranging in age from 33 to 74 years. Ovarian tissue sections were evaluated with OSE markers (keratin, β-catenin, E- and N-cadherin); markers of proliferation (proliferating cell nuclear antigen [PCNA], phosphorylated histone H3 [phospho-H3], and phosphorylated retinoblastoma [pRb]); or labels of collagen and basement membrane. As is evident in vitro, both monkey and human OSE were positive for keratin, β-catenin, and N-cadherin in vivo. Brushing of the ovaries partially removed the OSE without causing tissue damage or adhesions, and it increased the frequency of PCNA, phospho-H3, and pRb in the remaining OSE. As many as 50% of cells in brushed regions were marked, compared to fewer than 0.1% of cells in nonbrushed areas. Brushing did not induce the proliferation of underlying stromal cells. Further studies confirmed that the residual OSE was taking part in a true mitotic response (beyond merely transitioning from G1 to S phase). Proliferation of the OSE correlated more closely with brushing than with specific cell morphology. The investigators conclude that, because the OSE is able to undergo proliferative repair, its normal regulation might contribute to the development of EOC. It remains unclear whether the OSE is a necessary part of ovarian function, or whether abnormalities in the OSE contribute to ovarian defects such as polycystic ovary syndrome or infertility.