Members of the Ovarian Cancer Research Program on World Ovarian Cancer Day with Ottawa Mayor Jim Watson, May 2013
There are a number of research projects currently active in the Vanderhyden lab, and a brief description of each is provided below.
Mouse Models of Ovarian Cancer
Animal models that spontaneously develop cancer can help us understand the process of tumour formation and can aid in the investigation of novel prevention and treatment strategies. Recently, we have developed several mouse models of ovarian cancer to assist in our understanding of this disease. Our first model, developed through collaboration with scientists at the Fox Chase Cancer Center, is a transgenic model in which mice predictably develop epithelial ovarian cancer. While these mice develop ovarian cancer at an early age, they are useful for the testing of potential therapeutics, including novel oncolytic viruses. Subsequently, we have developed two additional mouse models of ovarian cancer which allow us to control the timing of disease initiation. These models are based on the Cre-lox system and the conditional activation of oncogenes or inactivation of tumour suppressors following the intra-bursal injection of adenoviral vectors expressing cre recombinase. These models are proving to be useful for the study of early lesions of disease and the response of disease initiation and progression to changes in the hormonal status of the model animals.
Effects of reproductive and genetic factors on ovarian cancer initiation and progression
The majority of ovarian cancers arise from the surface cells of the ovary, but the cellular and molecular events associated with early development of ovarian cancer are poorly understood. Epidemiologic evidence has identified a variety of reproductive factors that increase the risk of ovarian cancer, such as ovulation and certain hormones, notably estrogen. In addition, aging and hereditary risk (family history) are associated with the more frequent incidence of pre-cancerous structures in the ovary. The mechanisms by which these factors enhance the risk of ovarian cancer are unknown. The goal of this project is to address how ovarian cancers begin, with particular emphasis on reproductive and genetic factors that have been implicated in the initiation or progression of ovarian cancer, especially estrogen and a family history of the disease due to inheritance of BRCA1 mutations. We are examining the characteristics of the ovarian surface cells, determining how these cells transition to become cancer cells, and investigating how reproductive and genetic factors, such as estrogen, menopause and BRCA1 mutation, may promote the development of ovarian cancer by manipulating the behaviour of these surface epithelial cells.
Progenitor cells in the ovarian surface epithelium
Stem/progenitor cells in a variety of tissues have been found to play a role in tissue wound repair. We have identified a unique subset of mouse ovarian surface epithelial cells that have progenitor cell characteristics and that we hypothesize play a role in ovulatory wound repair. We are investigating the mechanisms by which these cells are regulated in number and function during ovulation and exploring if these cells are more susceptible to transformation into cancer cells.
Chromatin remodelling proteins involved in cellular differentiation
The switch from a proliferative to a differentiated state requires a cell to undergo sweeping changes in gene expression that is dependent on global chromatin remodelling within the nucleus. ISWI or SWI2/SNF2 proteins constitute the catalytic subunit of chromatin remodelling complexes that alter nucleosome positioning to regulate gene expression. We are collaborating with Dr. David Picketts to investigate the expression and function of Snf2h and Snf2l, chromatin remodelling proteins that seem to play a role in regulating cellular proliferation vs differentiation. As normal differentiation of granulosa cells is essential for female fertility, this project aims to examine the expression and function of the Snf2h and Snf2l genes during follicle development and corpus luteum formation, and to develop an animal model of infertility by disrupting the normal differentiation process in granulosa cells. We are also investigating the function of these proteins in ovarian cancer cells.
The Kit tyrosine kinase receptor and ovarian cancer
Growth factor/receptor autocrine loops are important features of some cancers. We have found that the c-kit protooncogene, which encodes the Kit tyrosine kinase receptor, is expressed in ovarian tumour cells, but not in normal ovarian surface epithelial cells, the cellular source of most ovarian cancers. Using cultures of normal human, rat and mouse surface epithelial cells and ovarian cancer cell lines, we are investigating epithelial-stromal cell interactions, epithelial-extracellular matrix interactions, and the role of Kit signalling in ovarian tumour induction, progression and chemosensitivity. Ovarian tumours are being screened to assess the diagnostic and prognostic value of Kit expression. As a consequence of these in vitro studies, we recently completed a U.S. Gynecologic Oncology Group clinical trial administering the Kit inhibitor Gleevec to ovarian cancer patients.
Please explore the page on lab members for more information about the lab members and their research projects.