Ovarian cancer has the highest mortality rate among all gynecologic malignancies. Therefore, identification of factors responsible for its accelerated cancer growth is of critical importance and may lead to development of novel therapeutic targets. Src,a non-receptor tyrosine kinase, is over-expressed and activated in a majority of late-stage ovarian tumors. Src mediates biological functioning of both tumor and tumor-associated endothelial cells, and promotes intercellular signaling responsible for tumor progression and metastasis. In addition, Src has proven to be a critical player in tumor angiogenesis and this is achieved mainly by activating pathways that lead to the secretion of VEGF, IL-8 and IL-6. The effect of stress on immunological parameters in cancer has been previously described. Little is known, however, about other mechanisms by which stress factors can affect the growth and progression of cancer. Stress activates the autonomic nervous system (ANS) and the hypothalamic-pituitary-adrenal (HPA) axis via the central nervous system. Activation of the ANS results in the release of catecholamines from the sympathetic nerves and adrenal glands causing a fight-or-flight stress response that may lead to the promotion of angiogenesis, acceleration of tumor growth and the invasion and migration of tumor cells. However, the mechanisms underlying these observations are not fully understood. I propose the hypothesis that catecholamines promote tumor growth and progression by P-adrenergic receptor mediated activation of Src in ovarian cancer cells. The following specific aims are designed to test this hypothesis.
Specific Aim 1. To determine the mechanisms and cellular consequences of catecholamine-induced Src activation by analyzing changes in RNA/Protein expression profile of tumor cell cultures with specific agonists and antagonists.
Specific Aim 2. To determine the requirement for Src activation for acceleration of tumor growth and metastasis in an in vivo setting using physiological and pharmacological stress models. Together, these experiments will provide important insights regarding stress-induced acceleration in tumor growth and the mechanisms underlying these deleterious effects. These studies will provide a better understanding of the crosstalk between growth factor receptor tyrosine kinase pathway and p-adrenergic receptor pathway and elucidate their interactions that result in progression of ovarian cancer growth and metastases
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