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Mouse Models of Ovarian Cancer
The study of ovarian carcinogenesis has been limited by the lack of appropriate tumor models. Presently, there are no developed experimental systems that recapitulate genetic changes that occur during ovarian carcinoma initiation or simulate the complex interactions between ovarian surface epithelial and stromal cells. The focus of our current research involves developing mouse models for early and metastatic ovarian cancer. We are developing mouse models in which defined multiple genetic lesions can be introduced into mouse ovarian stromal and/or surface epithelial cells in culture or in mouse ovaries. This system is based on avian RCAS virus delivery to the cells that are programmed to express the avian TVA receptor under the control of a tissue-specific promoter. The expression of the TVA receptor in mouse ovarian cells renders the cells susceptible to infection with RCAS viruses. RCAS vectors can be designed to carry oncogenes, marker genes, Cre recombinase, or activators of inducible systems into the TVA receptor-expressing cells. Various candidate genes that are thought to play a role in ovarian cancer can be introduced simultaneously or sequentially into mouse ovarian cells. Since multiple genes can be delivered to the same cell, it is possible to study the collaboration of biochemical pathways in ovarian cancer induction and progression.
Functional Characterization of FOXC2 in Ovarian Cancer Progression
FOXC2 was identified as one of the candidate metastasis genes in our differential expression screen between primary and metastatic mouse ovarian cancer cell lines. FOXC2 is a transcription factor that plays a critical role in specifying mesenchymal cell fate during embryogenesis. We showed that the FOXC2 protein is highly expressed in a subset of human ovarian cancer cell lines and primary ovarian carcinomas. In order to identify the potential function of FOXC2 in ovarian cancer, we ectopically expressed FOXC2 in several mouse ovarian cancer cell lines that normally have low levels of the FOXC2 protein. Overexpression of FOXC2 resulted in increased ovarian cancer cell proliferation, induction of spindle-like morphology, loss of contact inhibition, and anchorage-independent proliferation. Subcutaneous and intraperitoneal injection of FOXC2-transduced ovarian cancer cells into nude mice resulted in enhanced tumor growth in comparison to GFP-transduced cells. Consistent with the proposed role of FOXC2 in epithelial-mesenchymal transition, the cell lines and tumors that overexpress FOXC2 exhibited loss of the cell adhesion molecules E-cadherin and β-catenin. We are currently exploring the role of FOXC2 in ovarian cancer cell differentiation.
Ovulatory Wound Repair in a Mouse Model
Epidemiologic studies show a direct correlation between the number of ovulatory cycles and the risk of ovarian cancer, suggesting that ovulation may play a role in ovarian carcinogenesis. It is thought that the repair of the ovulatory wound results in rapid proliferation of the ovarian surface epithelial (OSE) cells, which may increase the frequency and accumulation of spontaneous mutations. Additionally, ovulation may lead to structural disorganization or entrapment of OSE cells in the underlying stroma with subsequent formation of inclusion cysts. In order to elucidate the sequence of events involved in the pathogenesis of ovarian cancer, we conducted a thorough analysis of morphologic changes in the OSE and underlying stroma during the process of ovulation. This was accomplished using traditional immunohistochemistry (IHC) and whole-ovary IHC, a method that was devised in our laboratory. We determined that cells on the ovarian surface proliferate most extensively during antral follicle growth. Cell proliferation is less extensive during ovulatory wound repair and corpus luteum formation, and is almost nonexistent in the areas distant from follicular activity. Rather than inducing a wave of new cell proliferation, we showed that ovulatory wound repair primarily involves a highly organized migration of epithelial and stromal cells at the wound edge.
Functional Characterization of BRCA1-Associated Ovarian Cancer Genes
Understanding the underlying genetic changes that drive ovarian cancer progression could have a major impact on the diagnosis and treatment of the disease. One of the pathways known to play a role in ovarian cancer development is the BRCA pathway. Using comparative oncogenomics in BRCA1-associated human tumors and mouse models, we identified several BRCA1-associated candidate cancer genes. We are currently testing the roles of these genes in the pathophysiology of BRCA-associated ovarian cancers. These genes have the potential to serve as biomarkers of clinical response to therapies that target the BRCA pathway and thus could have a major impact on the clinical management of hereditary ovarian cancers as well as sporadic ovarian cancers that have defective components of the BRCA pathway.