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

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 (AT1aÀ/À) 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 AT1aÀ/À mice with reduced expression of VEGFa. In AT1aÀ/À 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. The renin-angiotensin system (RAS) plays important roles in the regulation of cardiovascular homeostasis and blood pressure. 1 Many pathophysiological activities of angiotensin II (AII) are known to be mediated by the seven transmembrane receptors. Two major subtypes of AII receptors, namely AT1 receptor and AT2 receptor, have been identified, with the former having receptor subtypes, AT1a and AT1b. 2 Most of AII functions in the cardiovascular system are mediated through the AT1 receptor, and in rodents they are mediated through the AT1a receptor. [3][4][5][6] Recently, many reports have suggested that AII is involved in other functions, such as apoptosis, vascular remodeling, and inflammation. 7-9 As regards vascular remodeling, several studies have shown that AII promotes proliferation, migration, and growth factor synthesis in several types of vascular cells, including smooth muscle cells and pericytes. [10][11][12][13] Other studies have also investigated the angiogenic effects of exogenous AII in vivo angiogenesis models. 14-17 Furthermore, recent studies have revealed local expression of several components of the RAS in various cancer cells and tissues. 18 A large-scale clinica...

The renin-angiotensin system meets the hallmarks of cancer

“…22 In 2007, Imai and colleagues determined that AT1R-induced vascular endothelial growth factor a (VEGFa) signalling, in both host and tumour tissues, is one of the key regulators of tumour growth and tumour-associated angiogenesis. 23 The role of AT2R in cancer inflammation and angiogenesis is less clear. A recent study demonstrated that the inhibition of AT2R delays tumour growth by impairing VEGF expression and that tumours inserted into AGTR2-knockout mice demonstrate faster growth, which was related to higher VEGF production in stromal cells.…”

Overexpression of ACE2 produces antitumor effects via inhibition of angiogenesis and tumor cell invasion in vivo and in vitro

“…Importantly, the local RAS system contributes significantly to tumor angiogenesis and progression (9)(10)(11). Studies have shown that ACEI reduces non-small cell lung cancer (NSCLC) growth and angiogenesis (12,13) and that lung metastases are reduced by ACEI and angiotensin Ⅱ type 1 receptor blocker (ARB), via inhibition of MMP-2 expression in mice bearing Lewis lung carcinoma (14). Gallagher well as reduce vascular endothelial growth factor expression in human lung cancer xenografts, thereby inhibiting tumor angiogenesis (16).…”

Expression of AT1 and AT2 angiotensin receptors in astrocytomas is associated with poor prognosis

“…Previous reports have shown that the stimulation of this receptor augments VEGF expression in various tumoral and non-tumoral tissues and that its blockage inhibits VEGF expression in gliomas and other tissues (Chua et al, 1998;Tamarat et al, 2002;Arrieta et al, 2005;Imai et al, 2007). In addition, AT1 selective blockage inhibits cell proliferation and neovascularisation in experimental C6 rat glioma (Rivera et al, 2001;Arrieta et al, 2005), which is known to express AT1 (Rivera et al, 2001;Fogarty et al, 2002).…”

“…It has been shown that when murine Lewis lung carcinoma (LLC) cells -which express AT1 -are implanted subcutaneously into wild-type mice, they develop tumours that exhibit intense angiogenesis and induction of VEGF. However, when LLC cells are implanted in AT1a gene-deficient (AT1aÀ/À) mice, tumour growth and tumour-associated angiogenesis are reduced, with reduced expression of VEGF (Imai et al, 2007). Coincidentally, VEGF is rather important in GM pathophysiology: a critical difference between a low-and high-grade astrocytoma is the increase in VEGF-induced vascular density (Yao et al, 2001).…”