o-(chloroacetylcarbamoyl)fumagillol and candesartan-cilexetil

Although the renin angiotensin system (RAS) is a major regulator of vascular homeostasis, the role of the RAS in tumor angiogenesis is little understood. Here we show that host angiotensin II (ATII) type 1 (AT1) receptor plays an important role in angiogenesis and growth of tumor cells engrafted in mice. Subcutaneous B16-F1 melanoma-induced angiogenesis as assessed by tissue capillary density and microangiography was prominent in WT mice but was reduced in AT1a receptor-deficient (AT1a-/-) mice. Consequently, tumor growth rate was significantly slower, and the mouse survival rate was greater, in AT1a-/- mice than in WT mice. Tumor growth was also reduced in WT mice treated with TCV-116, a selective blocker of AT1 receptor. Because the beta-galactosidase gene was inserted into the AT1a gene locus in AT1a-/- mice, the site of beta-galactosidase expression represents the AT1a receptor expression in these mutant mice. In tumor-implanted AT1a-/- mice, the major site of the beta-galactosidase expression was macrophages in tissues surrounding tumors. Moreover, the number of infiltrated macrophages was significantly lower in AT1a-/- mice than in WT mice, and double-immunofluorescence staining revealed that these macrophages expressed VEGF protein intensively. Therefore, the host ATII-AT1 receptor pathway supports tumor-associated macrophage infiltration, which results in enhanced tissue VEGF protein levels. The host ATII-AT1 receptor pathway thereby plays important roles in tumor-related angiogenesis and growth in vivo.

Topics: Animals; Benzimidazoles; Biphenyl Compounds; Cyclohexanes; Endothelial Growth Factors; Intercellular Signaling Peptides and Proteins; Lymphokines; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Neoplasms, Experimental; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Receptor, Angiotensin, Type 1; Receptors, Angiotensin; Sesquiterpenes; Tetrazoles; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors