Angiotensin type 1a receptor signaling-dependent induction of vascular endothelial growth factor in stroma is relevant to tumor-associated angiogenesis and tumor growth.
Angiotensin II is a multi-functional bioactive peptide and recent reports have suggested that angiotensin II is a proangiogenic growth factor. A retrospective cohort study revealed that angiotensin converting enzyme inhibitors decreased cancer risk, however, the precise mechanism is unknown. We hypothesized that endogenous angiotensin II plays a crucial role in tumor-associated angiogenesis. Tumors implanted in the subcutaneous tissue of wild-type mice developed intensive angiogenesis with vascular endothelial growth factor (VEGF) induction in tumor stroma. AT1a receptor (AT1a-R), but not AT1b receptor or AT2 receptor was expressed in tumor stroma and systemic administration of an AT1-R antagonist reduced tumor-associated angiogenesis and VEGF expression in tumor stroma. Angiotensin II up-regulates VEGF expression through the pathway including protein kinase C, AP-1 and NF-kappaB in fibroblasts, the major cellular component of tumor stroma. VEGF is a major determinant of tumor-associated angiogenesis in the present model, since angiogenesis was markedly reduced by either a VEGF neutralizing antibody or a VEGF receptor kinase inhibitor. Compared with the wild-type, tumor-associated angiogenesis was reduced in AT1a-R null mice, with reduced expression of VEGF in the stroma, and this reduction in AT1a-R null mice was not inhibited by an AT1-R antagonist. These suggest that host stromal VEGF induction by AT1a-R signaling is a key regulator of tumor-associated angiogenesis and tumor growth. AT1a-R signaling blockade may be a novel and effective therapeutic strategy against cancers.
Fujita
Mamoru
M
Department of Pharmacology, Kitasato University School of Medicine, Graduate School of Medical Sciences, Kitasato 1-15-1, Sagamihara, Kanagawa 228-8555, Japan.
Hayashi
Izumi
I
Yamashina
Shohei
S
Fukamizu
Akiyoshi
A
Itoman
Moritoshi
M
Majima
Masataka
M
D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047228:Angiotensin II Type 1 Receptor Blockers; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D005347:Fibroblasts; D017706:Lisinopril / Q000494:pharmacology; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000503:physiopathology*; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D012509:Sarcoma / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction / Q000502:physiology; D013777:Tetrazoles / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D016328:NF-kappa B; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D018808:Transcription Factor AP-1; D042461:Vascular Endothelial Growth Factor A; D000804:Angiotensin II; D017706:Lisinopril; D011493:Protein Kinase C; D007703:Peptidyl-Dipeptidase A; C077793:candesartan cilexetil