Hypoxia: Impact on Src Signaling and Prostate Cancer

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 DESCRIPTION (provided by applicant): Prostate cancer is the most commonly diagnosed cancer in North America and the leading cause of cancer death in men. Metastasis is the primary cause of therapeutic failure in prostate cancer patients; resulting in poor prognosis and high mortality. Hypoxia, a common feature of most solid tumors including prostate cancer, has long been associated with enhanced metastasis and poor patient outcome. Hypoxia arises in tumors because the aggressive growth of neoplastic cells and associated over-expression of pro-angiogenic factors leads to aberrant vascular networks that are incapable of adequately delivering nutrients and removing waste products. As a consequence tumor cells can experience oxygen deprivation at the limit of oxygen diffusion (chronic or diffusion-limited hypoxia) or due to intermittent blood flow fluctuations (acute or perfusion-limited hypoxia). Both have been linked to enhanced tumor cell spread though their relative importance has not been unequivocally resolved. Evidence indicates that oxygen deficiencies in tumors can directly impact critical tumor cell functions critical to the metastatic phenotype including proliferation, survival, invasion, and induction of angiogenesis. The key hypoxia-regulated transcriptional factor HIF1 drives expression of many of the genes associated with these cancer cell functions. The Src family kinases (SFKs) are a family of non-receptor tyrosine kinases that are frequently hyper-activated in human cancers. In prostate cancer they contribute to increased aggressiveness and are associated with hormone insensitivity and metastasis. Src signaling promotes not only an invasive tumor cell phenotype but also enhances angiogenesis and formation of bone metastases. Interestingly, our preliminary evidence indicates that hypoxia is able to promote Src signaling, a less well-recognized finding. The goals of this proposal are to (i) determine the relative impact of acute and chronic hypoxic exposures on SFK activity and metastatic potential of prostate cancer cells in vitro and in vivo, (ii) examine the hypoxia-mediated HIF1-Src signaling pathways, and (iii) assess the ability of clinically employed small molecule Src inhibitors to impair hypoxia-induced metastasis. We believe that treatment options such as Src targeting strategies that interfere with the process of metastasis will have significan impact on cancer therapy outcomes and related mortality. Since metastasis has been linked both clinically and experimentally to hypoxia gaining a better understanding of how the varying oxygen deprivations that can occur in solid tumors impact metastasis-associated signaling and behavior should ultimately lead to the development of novel treatment options in the future.