Ovarian cancer is the leading cause of death among women with gynecologic malignancies. Due to poor survival of women with epithelial ovarian cancer, identification of factors responsible for accelerated cancer growth may lead to development of novel therapeutic approaches. Stress can elicit alterations of immunological, neurochemical, and endocrinological functions. To date, most of the research dealing with stress and tumor growth has focused on suppressed immunity; however, progressive growth of cancer is influenced by many other factors including blood supply to growing tumors (angiogenesis). There has been little investigation of the effect of stress mediators such as norepinephrine and epinephrine on angiogenesis. Vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8) are key factors that can stimulate tumor angiogenesis. We have compelling preliminary data that catecholamines can directly increase the production of pro-angiogenic cytokines such as VEGF and IL-8 by ovarian cancer cells and this effect can be blocked by using inhibitors of beta-adrenergic receptors. This project is designed to examine the effects of stress related mediators (norepinephrine, epinephrine, and cortisol) on secretion of pro-angiogenic cytokines by ovarian cancer cells and their resultant effects on cancer progression. We have designed a series of experiments that will determine the underlying mechanisms and pathways by which stress mediators can achieve these effects. We will also determine the in vivo effects of stress mediators on ovarian cancer growth and angiogenesis, and the effect of specific methods to block these deleterious effects using an in vivo orthotopic mouse model of ovarian cancer metastasis. Findings of this study could lead to identification of novel mechanisms underlying accelerated ovarian cancer growth and therefore may lead to new therapeutic approaches.
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