Roles for host and tumor angiotensin II type 1 receptor in tumor growth and tumor-associated angiogenesis

• Published in: Laboratory investigation 2007-02, Vol.87 (2), p.189-198
• Main Authors: Imai, Nozomi, Hashimoto, Tatsuo, Kihara, Minoru, Yoshida, Shin-ichiro, Kawana, Ichiro, Yazawa, Takuya, Kitamura, Hitoshi, Umemura, Satoshi
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - antagonists & inhibitors; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Analysis of Variance; angiogenesis; angiotensin II; Animals; AT1 receptor; Benzimidazoles - pharmacology; Biological and medical sciences; Biotechnology; Biphenyl Compounds - pharmacology; Blotting, Western; Carcinoma, Lewis Lung - metabolism; Carcinoma, Lewis Lung - physiopathology; Enzyme-Linked Immunosorbent Assay; Fundamental and applied biological sciences. Psychology; Immunohistochemistry; Investigative techniques, diagnostic techniques (general aspects); Laboratory Medicine; Male; Medical sciences; Medicine; Medicine & Public Health; Mice; Mice, Inbred C57BL; Mice, Knockout; Neovascularization, Pathologic - metabolism; Neovascularization, Pathologic - physiopathology; Pathology; Radioimmunoassay; Renin-Angiotensin System - drug effects; Renin-Angiotensin System - physiology; research-article; Reverse Transcriptase Polymerase Chain Reaction; RNA, Small Interfering - genetics; Signal Transduction - drug effects; Signal Transduction - physiology; Tetrazoles - pharmacology; tumor growth; Vascular Endothelial Growth Factor A - metabolism; VEGF
• ISSN: 0023-6837; 1530-0307
• DOI: 10.1038/labinvest.3700504

Angiotensin II (AII) is a multifunctional bioactive peptide, and host renin-angiotensin system (RAS) is closely associated with tumor growth. Recent reports have described that AII is a proangiogenic growth factor, and that Angiotensin II type 1 (AT1) receptor antagonists reduce tumor growth and tumor-associated angiogenesis. In this paper, we investigated the participation of AT1 receptor-signaling in cancer progression using murine Lewis lung carcinoma (LLC) cells, which express AT1 receptor, and AT1a receptor gene-deficient (AT1a−/−) mice. When LLC cells were implanted subcutaneously into wild-type (WT) mice, developed tumors showed intensive angiogenesis with an induction of vascular endothelial growth factor (VEGF) a. Compared with WT mice, tumor growth and tumor-associated angiogenesis was reduced in AT1a−/− mice with reduced expression of VEGFa. In AT1a−/− mice, administration of the AT1 receptor antagonist, TCV-116, showed further reductions of tumor growth, tumor-associated angiogenesis, and VEGFa expression. In vitro study, the expression of VEGFa mRNA and the production of VEGFa protein in LLC cells were significantly increased by AII, which were cancelled by AT1 receptor antagonist, CV-11974. Although the expression of other angiogenic factors, such as angiopoietin-1, angiopoietin-2, epidermal growth factor, and VEGF receptor 2 mRNA, was also investigated in tumor tissues, the expression of VEGFa was most correlated with tumor size among those other angiogenic factors. VEGFa induction by AT1 receptor-signaling in both host and tumor tissues is one of key regulators of tumor growth and tumor-associated angiogenesis. In conclusion, tumor tissue RAS as well as host tissue RAS were found to have an important role in tumor growth. AT1 receptor-signaling blockade may be a novel and effective target in the treatment of cancer.