The rhesus macaque: a unique and compelling model for human endometriosis-associated ovarian carcinomas

Abstract

Objectives: Clear cell ovarian carcinoma and endometrioid ovarian carcinoma (EnOC) are considered endometriosis-associated ovarian cancers (EAOCs). Given no higher order animal model currently exists for these cancers, we propose a novel animal model, the rhesus macaque (Macaca mulatta), for better understanding malignant transformation from endometriosis to EAOCs. Methods: The Wisconsin National Primate Research Center (WNPRC) maintains a multigenerational colony of Indian-derived rhesus macaques with well-documented incidence of spontaneous endometriosis. WNPRC researchers developed a model in which estrogen receptor-a was knocked down in the hypothalamus (hypoER-a) of adult rhesus females. Standard hemotoxylin and eosin (HE) and progesterone receptor (PR). Results: Twelve animals were evaluated, 6 hypoER-a and 6 control. Age at necropsy and characteristics associated with rhesus endometriosis were comparable between groups. Endometriosis was present in 4/6 hypoER-a females but in only 1/6 controls. HypoER-a animals had endometriosis in the uterus (2 cases), cervix (1 case), fallopian tube (2), ovary (2) and colon (1). The control animal had endometriosis in the uterus. ARID1A was retained in all tissues tested, including cases with endometriosis. WT-1 was positive in both epithelium and stroma for all endometriosis lesions. ER- a was negative in HypoER-a but not control endometriosis; PR was patchy positive in normal endometrium. PAX-8 stained rhesus tissue as would be expected in human analogs. One EnOC was identified in a hypoER-a animal that also had endometriosis. Conclusions: We have successfully created a nonhuman primate model that increases endometriosis penetrance. We also demonstrated parity between rhesus and human female endometriosis and EAOC by gross and histologic examination. Immunohistochemistry demonstrates WT-1 consistently stains endometrial glands and stroma in endometriosis. There was one animal with an EAOC in association with endometriosis. The rhesus macaque poses a higher order animal model for ongoing research in EAOC.