Angiotensin type 1a receptor signaling-dependent induction of vascular endothelial growth factor in stroma is relevant to tumor-associated angiogenesis and tumor growth

Fujita, Masato; Hayashi, Izumi; Yamashina, Shohei; Fukamizu, Akiyoshi; Itoman, Moritoshi; Murakami, Masataka

doi:10.1093/carcin/bgh324

Cited by 134 publications

(115 citation statements)

References 42 publications

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“…In vivo, the level of VEGFa protein was significantly lower in AT1aÀ/À mice than in WT mice. Moreover, the level of VEGFa protein was significantly lower in AT-TCV than in AT-C. Fujita et al 26 showed the administration of an AT1 receptor antagonist did not suppress the expression of VEGFa in tumor tissues of AT1aÀ/À mice, which had no detectable AT1 receptor. Our study clearly demonstrated that the AT1 receptor was detected by western blot analysis in the LLC cells.…”

Section: Discussionmentioning

confidence: 99%

“…19 Although angiogenesis induced by ACE inhibitors has been reported, 20,21 ACE inhibitors have also been shown to inhibit tumor-associated angiogenesis in many previous studies. [22][23][24] Recently, some reports using AT1 receptor antagonist and AT1a receptor gene-deficient (AT1aÀ/À) mice have shown that the blocking of AT1a receptor-signaling inhibited growth of the following tumor cells: melanoma, 25 lung, 26 prostate, 27 renal cell carcinoma, 28 and pancreas. 29 These studies suggested that AII induced tumor-associated angiogenesis by producing vascular endothelial growth factor (VEGF) a via AT1 receptor in host-derived stroma.…”

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confidence: 99%

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

Imai

Hashimoto

Kihara

et al. 2007

Laboratory Investigation

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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...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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

Imai

Hashimoto

Kihara

et al. 2007

Laboratory Investigation

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“…126 Ang II acts through AT1Rs to enhance vascular endothelial growth factor expression resulting in endothelial cell proliferation, migration and angiogenesis. 127,128 Activation of AT1R is also reported to induce inflammatory cytokines and chemokines through mitogen-activated protein kinase, reactive oxygen species and nuclear factor-kB pathways 129,130 (Figure 2). All these processes mediated by AT1 are important in the induction and progression of cancer.…”

Section: Anticancer Effect Of Aceismentioning

confidence: 99%

Reinventing the ACE inhibitors: some old and new implications of ACE inhibition

2009

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Since their inception, angiotensin-converting enzyme (ACE) inhibitors have been used as first-line therapy for the treatment of cardiovascular and renal diseases. They restore the balance between the vasoconstrictive salt-retentive and hypertrophy-causing peptide angiotensin II (Ang II) and bradykinin, a vasodilatory and natriuretic peptide. As ACE is a promiscuous enzyme, ACE inhibitors alter the metabolism of a number of other vasoactive substances. ACE inhibitors decrease systemic vascular resistance without increasing heart rate and promote natriuresis. They have been proven effective in the treatment of hypertension, and reduce mortality in congestive heart failure and left ventricular dysfunction after myocardial infarction. They inhibit ischemic events and stabilize plaques. Furthermore, they delay the progression of diabetic nephropathy and neuropathy and act as antioxidants. Ongoing studies have elucidated protective roles for them in both memory-related disorders and cancer. INTRODUCTIONIn recent years, stressful and fiercely competitive lifestyles and food habits have compounded the problems of hypertension. Long-standing and stressful, progressively rising hypertension can lead to many disorders, including myocardial infarction (MI), cerebrovascular events, congestive heart failure, peripheral arterial insufficiency, premature mortality 1 and renal dysfunction leading to glomerulosclerosis and kidney artery aneurysm. 2 A number of therapies are available, but angiotensin-converting enzyme (ACE) inhibitors have been the preferred first-line therapy for hypertension, congestive heart failure, left ventricular (LV) systolic dysfunction and MI. 3,4 ACE inhibitors (ACEis) have been in use for the past two decades, and the interest in them is still growing. Recently, the discovery of domain-selective ACEis and new members of the renin-angiotensin system (RAS) (that is, angiotensin-converting enzyme 2) have again fueled the interest of researchers. Some new studies have expanded the already impressive clinical profile of ACEis. This review traces some already known and new facets of ACE inhibition and introduces new advances in the designing of a new generation of ACEis.

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“…Increasing evidence suggests that angiotensin II signaling plays an important role in carcinogenesis (Fujita et al 2005;Ino et al 2006;Kanehira et al 2005;Suganuma et al 2005;Takagi et al 2002:Egami 2003. However, the specific role of AT 2 in carcinogenesis has not been rigorously elucidated.…”

Section: Discussionmentioning

confidence: 99%

Specific single chain variable fragment (ScFv) antibodies to angiotensin II AT2 receptor: evaluation of the angiotensin II receptor expression in normal and tumor-bearing mouse lung

et al. 2008

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SummaryTo gain insight into the mechanism by which angiotensin II type 2 receptor (AT 2 ) regulates carcinogen-induced lung tumorigenesis, we have newly developed anti-AT 2 single chain variable fragment (ScFv) antibodies using a rodent phage-displayed recombinant antibody library with various peptide fragments of the receptor protein, and investigated the expression of the AT 2 receptor protein. The specificity of the antibodies was verified using AT 2 over-expressing COS-7 cells and AT 2 naturally expressing PC12W cells. In control wild type mouse lung, a stronger immunoreactivity was observed in bronchial epithelial cells. A moderate immunoreactivity was detected in pulmonary vascular walls and vascular endothelial cells. In the lungs possessing tobacco-specific nitrosamine (NNK)-induced tumors, significantly increased AT 2 and AT 1 immunostaining was observed in adenomatous lesions. These data suggest that the increase in both receptors' expression in the alveolar epithelial cells may be accompanied with the onset of NNK-induced tumorigenesis and hence play important roles in lung tumorigenesis.

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Angiotensin type 1a receptor signaling-dependent induction of vascular endothelial growth factor in stroma is relevant to tumor-associated angiogenesis and tumor growth

Cited by 134 publications

References 42 publications

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

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

Reinventing the ACE inhibitors: some old and new implications of ACE inhibition

Specific single chain variable fragment (ScFv) antibodies to angiotensin II AT2 receptor: evaluation of the angiotensin II receptor expression in normal and tumor-bearing mouse lung

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