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Carcinogenesis Advance Access originally published online on January 6, 2005
Carcinogenesis 2005 26(2):271-279; doi:10.1093/carcin/bgh324
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Carcinogenesis vol.26 no.2 © Oxford University Press 2005; all rights reserved.

ARTICLE

Angiotensin type 1a receptor signaling-dependent induction of vascular endothelial growth factor in stroma is relevant to tumor-associated angiogenesis and tumor growth

Mamoru Fujita1,2, Izumi Hayashi1, Shohei Yamashina3, Akiyoshi Fukamizu4, Moritoshi Itoman2 and Masataka Majima1,*

1 Department of Pharmacology, 2 Department of Orthopaedic Surgery and 3 Department of Anatomy, Kitasato University School of Medicine and 1 Department of Molecular Pharmacology, Graduate School of Medical Sciences, Kitasato 1-15-1, Sagamihara, Kanagawa 228-8555, Japan and 4 Center for Tsukuba Advanced Research Alliance, Institute of Applied Biochemistry, University of Tsukuba, Tsukuba, Ibaraki 305-8572, Japan

* To whom correspondence should be addressed at: Department of Pharmacology, Kitasato University School of Medicine, Kitasato 1-15-1, Sagamihara, Kanagawa 228-8555, Japan. Tel: +81 42 778 8822; Fax: +81 42 778 7604; Email: en3m-mjm{at}asahi-net.or.jp

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-{kappa}B 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.


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