The effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on ovarian cancer progression

Among epithelial cancers, OC is unique with respect to the relatively undefined mechanisms of progression. The etiology and events of OC progression are among the least understood of all human malignancies, primarily due to the lack of appropriate animal models. Ovarian cancer has a higher level of mortality than any other type of gynecological malignancy. This mortality is due in part to the high degree of metastasis at the time of diagnosis. Greater than 90% of ovarian cancers are believed to arise from the single layer of epithelial cells that cover the surface of the ovary, however, factors that may enhance the progression of these types of lesions into an invasive and metastatic phenotype are currently unknown. 2,3,7,8,-Tetrachlorodibenzo- p-dioxin (TCDD) is an extremely toxic chemical pollutant, primarily due to its stable biochemical properties and extreme resistance to biodegradation. TCDD has been classified by the International Agency for Research on Cancer as a group 1 epigenetic human carcinogen. The work presented in this dissertation describes the molecular, cellular and physiological effects of TCDD on epithelial ovarian cancer in vitro and in vivo in efforts to better understand the mechanisms that chemicals utilize to modulate carcinogenesis. Collectively these data indicate that the progression of ovarian cancer may be modulated by TCDD due to: dysregulation of intracellular signaling proteins, advancement of ascites accumulation, increased tumor burden, hepatotoxicity, induction of enzymes known to promote systemic oxidative stress and immunotoxicity. These effects of TCDD are quite possibly linked to its ability to reduce the survival of mice burdened with ovarian cancer, thus a plausible mechanism of an acceleration of ovarian cancer progression.