27 - 30 May 2005

MODELING OVARIAN CANCER IN THE MOUSE Denise C. Connolly, Alexander Yu. Nikitin[†], Christine Williams, Kim Baxter-Jones, Xiang Hua, Harvey Hensley, Lora Hedrick Ellenson[‡] and Tom Hamilton Ovarian Cancer Program Fox Chase Cancer Center Philadelphia, PA 19111 USA [†] Deptartment. of Biomedical Sciences Cornell University Ithaca, NY 14853 USA [‡] Division of Gynecologic Pathology Department of Pathology Weill Medical College of Cornell University New York, NY 10021 USA

In women, the vast majority of ovarian tumors are of epithelial origin. If diagnosed at early stage, the prognosis for patients is quite good; however, most cases are not detected until the cancer is at advanced stage when the five-year survival rate drops to 30-40%.

Mouse models of many types of human cancer have been developed over the past two decades. The development of mouse models of human ovarian cancer has been delayed by both a lack of understanding of the disease process in humans and of the putative precursor cells of epithelial ovarian cancer (EOC). The lack of adequate animal models of EOC significantly delays advances in early detection and treatment of this disease.

We have developed a transgenic mouse model of EOC by expressing the transforming region of simian virus 40 (SV40) under transcriptional control of the 5’ upstream regulatory sequences of the Müllerian inhibitory substance type II receptor (MISIIR) gene. Approximately 50% of transgene positive TgMISIIR-TAg founder mice develop bilateral ovarian carcinomas. Histologically, these tumors are poorly differentiated carcinomas with occasional cysts and papillary structures present at the surface of the ovary. These tumors disseminate intraperitoneally, invade omentum and are frequently accompanied by the presence of bloody ascites similar to human ovarian carcinomas.

The epithelial origin of the ovarian tumors is supported by the detection of cytokeratins 8 and 19, and the absence of alpha-inhibin, a protein characteristically expressed in granulosa cells and most granulosa cell tumors. Cell lines routinely derived from ascites exhibit the properties of EOC, such as anchorage-independent growth, tumorigenicity in immunocompromised mice, expression of epithelial cell markers and organotropic implantation. Approximately 25-30% of male TgMISIIR-TAg transgenic founders develop Sertoli cell tumors. Although most female TgMISIIR-TAg transgenic founders succumb to disease prior to breeding, a stable transgenic line of EOC prone mice was established via an affected male TgMISIIR-TAg transgenic founder. Female mice of this transgenic line succumb to disease at approximately 5-6 months of age.

The availability of this mouse model of human EOC allows us to investigate the early stages and origin of the tumors and additional molecular alterations that contribute to of the disease process. In addition, we have developed in vivo imaging strategies using Magnetic Resonance Imaging (MRI) to detect tumor burden over time. The availability of this preclinical model and the techniques to monitor tumor burden in vivo will be very useful in the evaluation of potential therapeutic agents for treatment of EOC.

The identification and validation of the MISIIR gene promoter as a suitable promoter for directing transgene expression to the mouse ovary provides an important tool for further development of genetically engineered mouse models of ovarian cancer. Current studies are therefore focused on the development of the next generation of mouse models of human EOC by using this gene promoter to drive tissue-restricted expression of activated oncogenes (e.g., Akt2, STAT3, PI3Kinase, etc.) in combination with conditional inactivation of tumor suppressor genes (e.g., p53, BRCA1, etc.) known to be important in the development and progression of human EOC.

List of abstracts from the 3rd International Conference on the Female Reproductive Tract