RRC ID 42901
Author Imai N, Hashimoto T, Kihara M, Yoshida S, Kawana I, Yazawa T, Kitamura H, Umemura S.
Title Roles for host and tumor angiotensin II type 1 receptor in tumor growth and tumor-associated angiogenesis.
Journal Lab. Invest.
Abstract 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.
Volume 87(2)
Pages 189-98
Published 2007-2
DOI 10.1038/labinvest.3700504
PII 3700504
PMID 17318197
MeSH Adaptor Proteins, Signal Transducing / antagonists & inhibitors Adaptor Proteins, Signal Transducing / genetics Adaptor Proteins, Signal Transducing / metabolism* Analysis of Variance Animals Benzimidazoles / pharmacology Biphenyl Compounds / pharmacology Blotting, Western Carcinoma, Lewis Lung / metabolism Carcinoma, Lewis Lung / physiopathology* Enzyme-Linked Immunosorbent Assay Immunohistochemistry Male Mice Mice, Inbred C57BL Mice, Knockout Neovascularization, Pathologic / metabolism Neovascularization, Pathologic / physiopathology* RNA, Small Interfering / genetics Radioimmunoassay Renin-Angiotensin System / drug effects Renin-Angiotensin System / physiology* Reverse Transcriptase Polymerase Chain Reaction Signal Transduction / drug effects Signal Transduction / physiology* Tetrazoles / pharmacology Vascular Endothelial Growth Factor A / metabolism
IF 3.684
Times Cited 53
Human and Animal Cells