Understanding the role of inflammation in ovarian carcinogenesis; using gene-array technology to detect differential expression patterns of inflammation-specific genes in normal and malignant ovarian epithelial cells.
Ovarian epithelial cell cancer is a leading cause of death from gynecological malignancies and the fourth leading cause of cancer in women. Epidemiological and clinical studies suggest that there is a link between inflammation and ovarian epithelial cell cancer. For example consumption of an antioxidant-rich diet or regular consumption of nonstreoidal anti-inflammatory drugs (NSAID)s decreases the risk of developing ovarian cancer.
To understand how inflammation can lead to ovarian epithelial cell cancer we are investigating the expression of gene and protein levels of known inflammatory signaling mediators in normal and malignant ovarian epithelial cells. We use gene and protein array technologies. Our preliminary studies suggest that the proinflammatory cytokine TNFa and TNFa signaling mediators are overexpressed in ovarian epithelial cancer cell lines and the level of TNFa is elevated in ascites fluid of ovarian cancer patients. TNFa has an essential role in inflammation. Furthermore TNFa -/- mice are resistant to the development of benign and malignant skin tumors. To determine if disruption of tumor necrosis factor-alpha (TNFa) signaling affects the development and/or progression of ovarian epithelial cell cancer we established an immunocompetent (mice have intact immune system) mouse ovarian cancer model. In this model, if cultures of freshly isolated mouse ovarian surface epithelial cells (MOSE) are propagated in vitro for an extended period of time they spontaneously transform. When these MOSE propagated in vitro are introduced into host mice tumors of ovarian epithelial origin develop. Using this model we can study if MOSE cells derived from animals in which either the TNFa or the type I TNF receptor are knocked out generate tumors in syngeneic mice or if MOSE cells that give rise to tumors in syngeneic mice generate tumors in animals in which either the TNFa or the type I TNF receptor are knocked out.
One of the most commonly used anti-inflammatory agent aspirin has been shown to reduce the incidence of ovarian cancer by 40%. Long term administration of aspirin with the goal of preventing or decreasing the incidence of ovarian cancer however is not achievable as aspirin can lead to deleterious health problems such as gastrointestinal bleeding. There is a need to identify safe and effective alternatives to aspirin and other NSAIDs. We are in the process of testing the effect of alpha-lipoic-acid, a naturally occurring biological antioxidant on ovarian epithelial cell cancer.
The promise of our studies is to gain a better understanding of the role inflammation plays in ovarian cancer and help us reach our long-term goal of determining if anti-inflammatory therapies can be used to prevent and/or treat ovarian epithelial cell cancer.
