Role of host angiotensin II type 1 receptor in tumor angiogenesis and growth.
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.
Egami
Kimiyasu
K
Department of Cardiology, Nagoya University Graduate School of Medicine, Kurume, Japan.
Murohara
Toyoaki
T
Shimada
Toshifumi
T
Sasaki
Ken-Ichiro
K
Shintani
Satoshi
S
Sugaya
Takeshi
T
Ishii
Masahiro
M
Akagi
Teiji
T
Ikeda
Hisao
H
Matsuishi
Toyojiro
T
Imaizumi
Tsutomu
T
D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D003510:Cyclohexanes; D016228:Endothelial Growth Factors / Q000032:analysis; D036341:Intercellular Signaling Peptides and Proteins / Q000032:analysis; D008222:Lymphokines / Q000032:analysis; D008546:Melanoma, Experimental / Q000098:blood supply / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000098:blood supply* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000209:etiology*; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin / Q000032:analysis / Q000502:physiology*; D012717:Sesquiterpenes / Q000494:pharmacology; D013777:Tetrazoles; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D001562:Benzimidazoles; D001713:Biphenyl Compounds; D003510:Cyclohexanes; D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin; D012717:Sesquiterpenes; D013777:Tetrazoles; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C077793:candesartan cilexetil; D000077609:O-(Chloroacetylcarbamoyl)fumagillol