Characterization of rat ovarian adenocarcinomas developed in response to direct instillation of 7,12-dimethylbenz[a]anthracene (DMBA) coated suture

Human ovarian cancer is predominantly of epithelial cell origin (> 90% of malignant tumors) and most often presents at an advanced stage with poor prognosis. Most animal models of ovarian carcinoma yield thecal/granulosa cell tumors, rather than adenocarcinomas. Induction of adenocarcinoma in 10-45% of rats following an ovarian implantation of 7,12-dimethylbenz[a]anthracene (DMBA) coated silk suture has been reported. Here, DMBA of 99% purity was melted at 124 degrees C to impregnate a 1 cm length of sterile suture for direct ovarian implantation in Wistar Furth rats at 7 weeks of age. DMBA-treated ovaries showed a nearly complete loss of primary follicles and degeneration of granulosa cells at 16 weeks, consistent with the known toxic response of the ovary to direct DMBA application. No tumors were present. Untreated right ovaries and sham dimethyl sulfoxide-treated ovaries were normal. Ovarian tumors in DMBA-treated rats were first noted at 26 weeks post implantation reaching a cumulative tumor incidence of 77% (23/30) at 52 weeks. Controls showed no evidence of tumor at 52 weeks (0/31). Tumor histology was distributed as well differentiated adenocarcinoma (1/23), poorly differentiated adenocarcinoma (8/23), thecal/granulosa cell tumor (8/23), undifferentiated sarcoma (5/23) and one undifferentiated carcinoma with no adeno character. Tumors occasionally seeded to peritoneal mesentery, spleen and abdominal wall. Adenocarcinomas appeared to originate from the ovarian surface epithelium, with focal papillary extension into cystic space. Epithelial derived tumor cells positively react with antibodies to cytokeratin (8/8), epithelial cell adhesion molecule (Ep-CAM 5/5) and prostaglandin synthetase-1 (COX-1 4/4). Vimentin positive epithelial cells when present in adenocarcinomas (4/7), showed perinuclear staining, quite distinct from the uniformly stained stromal cells in thecal/granulosa cell tumors (8/8). The thecal/granulosa cell tumors were Ep-CAM negative (0/5) and weakly COX-1 positive (4/4). Thus, the DMBA suture model in rats yields epithelial derived tumors histologically similar to humans and should prove suitable for the testing of preventive or therapeutic agents.