Carcinogenesis Advance Access published online on January 6, 2005
Carcinogenesis, doi:10.1093/carcin/bgh324
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1 Department of Pharmacology, Kitasato University School of Medicine, Sagamihara, Kanagawa 228-8555, Japan; Department of Molecular Pharmacology, Graduate School of Medical Sciences, Sagamihara, Kanagawa 228-8555, Japan; Department of Orthopaedic Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa 228-8555, Japan
* To whom correspondence should be addressed. Angiotensin II is a multi-functional bioactive peptide, and the 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 has a crucial role in tumor-associated angiogenesis. Tumor implanted in the subcutaneous tissue of wild-type mice (WT) developed intensive angiogenesis with vascular endothelial growth factor (VEGF) induction in tumor stroma. AT1a receptor (AT1a-R), but not AT1b-R or AT2-R 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-
Received December 10, 2003
Revised September 3, 2004
Accepted October 26, 2004
CANCER BIOLOGY
Angiotensin type 1a receptor signaling-dependent induction of vascular endothelial growth factor in stroma is relevant to tumor-associated angiogenesis and tumor growth
2 Department of Pharmacology, Kitasato University School of Medicine, Sagamihara, Kanagawa 228-8555, Japan; Department of Molecular Pharmacology, Graduate School of Medical Sciences, Sagamihara, Kanagawa 228-8555, Japan
3 Department of Anatomy, Kitasato University School of Medicine, Sagamihara, Kanagawa 228-8555, Japan
4 Center for Tsukuba Advanced Research Alliance, Institute of Applied Biochemistry, University of Tsukuba, Tsukuba, Ibaraki 305-8572, Japan
5 Department of Orthopaedic Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa 228-8555, Japan;
Masataka Majima, E-mail: en3m-mjm{at}asahi-net.or.jp
Abstract 
B in fibroblasts, major cellular component of tumor stroma. VEGF is a major determinant for 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 WT, tumor-associated angiogenesis was reduced in AT1a-R-null mice with reduced expression of VEGF in 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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