STUDY ON MECHANISM OF TUMOR ANGIOGENESIS IN UROTHELIAL CANCERS AND SCREENING OF ANGIOGENIC INHIBITORS

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Tumor angiogenesis is essential for tumor growth and metastasis. Solid tumors depend on angiogenesis to grow larger than a few millimeters in diameter. To investigate the role of several angiogenic factors, such as b-FGF,VEGF,PDGF-A and TGF-alpha in angiogenesis in urothelial cancers, we examined the expression and localization of these angiogenic factors in patients with bladder cancers and renal cell carcinomas. Furthermore, tubulogenesis by VEGF and b-FGF of microvascular endothelial cells co-cultured with renal cancer cells was also examined by a three dimensional co-culture assay system. RT-PCR analysis detected mRNAs of b-FGF,VEGF,PDGF-A and TGF-alpha in 96%, 77%, 69% and 50% in renal cancers and 77%, 62%, 62% and 0% in bladder cancers, respectively. Immunohistochemical analysis revealed that b-FGF and VEGF were primarily localized in the nucleus and cytosol, respectively. Exogenous addition of b-FGF and VEGF increased tube formation of microvascular endothelial cells in a dose dependent manner in the three dimensional co-culture assay system. However, specific antibodies against b-FGF (10mug/ml) and VEGF (10mug/ml) completely inhibited the tube formation in the system, suggesting that neutral antibodies against angiogenic factors, including b-FGF and VEGF may suppress tumor growth by the inhibition of tumor angiogenesis. Recently, we observed that the expression of TGF-alpha increased as a function of tumor size in nude mice bearing bladder tumors, although the expression of TGF-alpha in the original bladder tumor was weak. Furthermore, we observed that bladder tumors which highly express PD-ECGF showed high tumor microvascular density determined by von-Willebrand factor. Thses results suggest that several angiogenic factors were involved in the multi-steps of tumor angiogenesis of urothelial cancers. Specific antibodies against these angiogenic factors may be clinically applicable to the cancer treatment.