Ovarian cancer has the highest mortality rate among gynecologic malignancies. Due to poor survival of women with epithelial ovarian cancer, identification of factors responsible for accelerated cancer growth may have significance for clinical outcomes. Stress can elicit alterations of immunological, neurochemical, and endocrinological functions. While most of the research dealing with stress and accelerated tumor growth has focused on suppressed immunity, during our initial funding period we have uncovered new mechanisms by which chronic stress affects the tumor microenvironment. We established that sympathetic nervous system (SNS) activation in response to chronic stress resulted in increased production of pro- angiogenic factors by tumor cells. This increase was responsible for promoting tumor vascularity and perfusion. These effects were mediated by the 22-adrenergic receptors (ADRB2) on tumor cells and were blocked by beta-antagonists. However, there is third member of the catecholamine family, dopamine, which is known to have anti-angiogenic effects, but it is decreased in response to chronic stress. This project is designed to characterize dopamine levels in ovarian cancer using chronic stress models as well as human ovarian cancers. Furthermore, we will determine the expression levels of dopamine receptors in both ovarian cancer and endothelial cells. We will also analyze the biological effects of dopamine replacement using our well-characterized orthotopic model of ovarian carcinoma. Findings of this study could lead to identification of novel mechanisms underlying accelerated ovarian cancer growth and therefore may lead to new therapeutic approaches.
Chronic stress can affect many aspects of health and is suspected to play a role in promoting cancer growth, but the underlying mechanisms are not well understood. Our studies are designed to provide a mechanistic understanding of how chronic stress promotes cancer growth and to devise strategies for overcoming these effects. The results from this work could be important for designing new methods of treatment of cancer patients.
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