Prostate cancer is the second leading cause of death from cancer in men in the U.S. and mortality from prostate cancer is invariably due to tumor metastasis. Our overall goals for the first competitive renewal application therefore continue to be to understand prostate cancer invasion and hematogenous metastasis. We have gleaned several insights from the previous four years of studying the role of vascularization and the physiological environment in promoting prostate cancer invasion and dissemination. This has led us to formulate five new hypotheses: (1) invasion is necessary but not sufficient, without vascularization, for hematogenous prostate cancer metastasis; (2) there are combinations of co-registered vascular, physiological and metabolic regions within solid tumors, which are most permissive for invasion and metastasis; (3) anti-angiogenic treatments attenuate or prevent metastasis; (4) there will be a reduction in the """"""""permissive"""""""" vascular, physiological and metabolic regions following treatment with anti-angiogenicagents; (5) endothelial cell - cancer cell interactions play a significant role in promoting invasion and metastasis from stressed physiological conditions of hypoxia and acidic pH found in solid tumors. We will continue to work with the human prostate cancer xenografts we selected during our first funding period. We will increase vascularization in solid tumors by creating transgenic cell lines over expressing VEGF A or bFGF, and reduce vascularization by treating solid tumors with the anti-angiogenic agents TNP-470 and endostatin. The technical advances we have made, such as obtaining co-registered maps of vascular volume, permeability, extracellular pH and metabolites will be applied to gain further insight into prostrate cancer metastasis. Our """"""""Metabolic Boyden Chamber"""""""" assay that was developed and optimized during the previous funding period now has an additional facet of a layer of endothelial cells incorporated between the matrigel layer and the cellular layer. This will allow, for the first time, the noninvasive investigation of the interaction between vascular endothelial cells and prostate cancer cells under various physiological conditions, simulating conditions found in solid tumors. The proposed studies will continue to identify vascular, physiological and metabolic characteristics that promote invasion and metastasis. This information is critical for developing strategies to prevent metastasis from prostate cancer.
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