17beta-estradiol accelerates tumor onset and decreases survival in a transgenic mouse model of ovarian cancer.

Epithelial ovarian cancer is thought to be derived from the ovarian surface epithelium (OSE) but often goes undetected in the early stages, and as a result, the factors that contribute to its initiation and progression remain poorly understood. Epidemiological studies have suggested that the female steroid hormones are involved in ovarian carcinogenesis and that women who use hormone replacement therapy are at increased risk of developing the disease. A novel transgenic mouse model of ovarian cancer (tgCAG-LS-TAg) was developed to examine the role of the female reproductive steroid hormones [17beta-estradiol (E(2)) and progesterone (P(4))] on the initiation, progression, and pathology of ovarian cancer. The mouse model uses the Cre-LoxP system to induce expression of the simian virus 40 large and small T antigens (SV40 TAg). After targeted induction of the oncogene in the OSE, mice develop poorly differentiated ovarian tumors, tumor dissemination to tissues within the abdominal cavity, and a subset develops hemorrhagic ascites. Treatment with P(4) had no impact on the disease, but E(2) altered the pathophysiology, resulting in an earlier onset of tumors, decreased overall survival time, and a distinctive papillary histology. Normal ovaries collected from mice treated with E(2), but lacking expression of SV40 TAg, displayed an increase in the areas of columnar and hyperplastic OSE cells compared to placebo-treated controls. A better understanding of the mechanisms by which E(2) alters the morphology of normal OSE cells and reduces survival in this mouse model may translate into improved prevention and treatment options for women using hormone replacement therapy.

Characterization of intraperitoneal, orthotopic, and metastatic xenograft models of human ovarian cancer.

Improvement of ovarian cancer patient outcome requires well-characterized animal models in which to evaluate novel therapeutics. Xenograft models are frequently used, but with little discussion of disease histology. The objectives of this study were to inject 11 ovarian cancer cell lines intraperitoneally (ip), and a subset intrabursally (ib; orthotopic), into nude mice and to analyze the resulting pathologies. Eight of 11 lines injected ip formed tumors within 3 months at variable rates with the following histological subtype distribution: one endometrioid, one serous, one clear cell, and five undifferentiated. Only mice injected with A2780-cp cells presented with ovarian-specific metastases (11 of 88), and the survival time of these animals was significantly shorter, which may be attributed to the higher proliferation rate as determined by Ki67 positivity. Additional analysis of the influence of the ovarian microenvironment on cell characteristics was conducted with ib injection of two cell lines (OVCA 429 and ES-2). The site of injection did not affect the tumor histology, the effect on proliferation was cell-type dependent, and the tumor take rate (cell survival) was negatively affected for OVCA 429 cells. The animal models described herein represent histologically distinct models of both early and late stage ovarian cancer useful for evaluation of therapeutics.