Chemoprevention of Bladder CA by soybean bioactive comp.

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DESCRIPTION (provided by applicant): This proposal is focused on the chemopreventive activity of soybean bioactive components on bladder cancer. The hypothesis is that increased dietary consumption of soybean bioactive components may serve as an effective nutritional regimen for the prevention of bladder cancer progression and metastasis by modulating bladder tumor angiogenesis, apoptosis and/or proliferation. The rationale for supporting this hypothesis is based on the followings: (1) Soy bioactive components exert their effects on anti-bladder cancer via both blood circulation and direct contact with the mucosa of the bladder, and (2) Our animal studies and in vivo mechanistic studies indicated that soy phytochemicals inhibited bladder tumor progression by inducing tumor cell apoptosis, inhibiting tumor proliferation and inhibiting tumor angiogenesis. In this proposal, three specific aims will be designed to test our hypothesis by using a clinically relevant orthotopic bladder model. Specific Aim 1 is to determine the effect of soybean components on orthotopic growth and/or metastasis of both well-differentiated, low metastatic (RT4) and poorly differentiated, highly metastatic (253J B-V) human bladder tumors. Soybean components (soy isoflavone-depleted soy protein, soy phytochemical concentrate, and soy genistin) will be evaluated for their effects on the growth and metastasis of both RT4 and 253J-B-V tumors in vivo. Specific aim 2 is to determine the effect of soybean components on the expression of tumor biomarkers that are related to tumor cell apoptosis and proliferation and tumor angiogenesis. These apoptotic and proliferation biomarkers include (a) apoptotic index and related apoptosis inducers (p53, p21/wafl, bax, TNF-alpha) and apoptosis repressors (bcl-2, bcl-xl), (b) proliferation index and cell cycle related cyclins (A, D, E) and cyclin-dependent kinases (cdks 2, 4, 6). Our in vitro microarray assays have suggested that markers that are related to angiogenesis network are among important genes that are significantly modulated by soy components. These angiogenic biomarkers include tumor angiogenic factors (VEGF, bFGF, angiopoietin-1) and anti-angiogenic factor angiopoietin-2. RT-PCR and immunohistochemistry followed by image analysis will be applied to determine the expression of above molecular markers. Specific aim 3 is to further elucidate mechanisms involved in the interactive affect of genes and soy bioactive components on bladder cancer modulation in vitro and in vivo by employing microarrayed cDNA chip technology. By using an oligonucleotide array containing sequences complementary to about 12,000 full-length human cDNAs, both dose-dependent and time-dependent mRNA expression patterns will be determined in both in vitro and in vivo samples. Some of these significantly different gene transcripts will be confirmed by RT-PCR. Results derived from the proposed studies by integrating nutrition, molecular biology and genetics in bladder cancer prevention research will be expected to provide significant insight into the utilization of dietary soy in the prevention of bladder cancer.