Journal 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 Fujita, Izumi Hayashi, Shohei Yamashina, Akiyoshi Fukamizu, Moritoshi Itoman and Masataka Majima

in Carcinogenesis

Volume 26, issue 2, pages 271-279
Published in print February 2005 | ISSN: 0143-3334
Published online February 2005 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgh324
Angiotensin type 1a receptor signaling-dependent induction of vascular endothelial growth factor in stroma is relevant to tumor-associated angiogenesis and tumor growth

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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-κB 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.

Keywords: ACE, angiotensin I-converting enzyme; Ang II, angiotensin II; AT1-R, AT1 receptor; AT2-R, AT2 receptor; DMEM, Dulbecco's modified Eagle's medium; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; GFX, bisindolylmaleimide; Hb, hemoglobin; MVD, microvessel density; MVA, microvessel area; PDTC, pyrrolidine dithiocarbamate; S-180, Sarcoma 180; VEGF, vascular endothelial growth factor

Journal Article.  6217 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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