Blockade of angiotensin AT1a receptor signaling reduces tumor growth, angiogenesis, and metastasis
Blockade of angiotensin AT1a receptor signaling reduces tumor growth, angiogenesis, and metastasis
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DOI：
10.1016/s0006-291x(02)00496-5
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发表时间：
2002-06-07
影响因子：
3.1
通讯作者：
Majima, M
中科院分区：
文献类型：
--
作者：
Fujita, M;Hayashi, I;Majima, M
据报道，血管紧张素II在体内刺激血管生成，而血管紧张素转换酶(ACE)抑制剂抑制血管生成。我们发现AT1受体(AT1-R)拮抗剂TCV-116在小鼠模型中抑制肿瘤生长、肿瘤相关血管生成和转移。饲料中加入约100 mg/kg/d的TCV-116可明显抑制S肉瘤细胞和纤维肉瘤细胞的生长。这种减少伴随着肿瘤相关血管生成的显著减少。同样的治疗方法也减少了静脉注射Lewis肺癌细胞的肺转移。TCV-116的上述作用与ACE抑制剂赖诺普利相当。逆转录聚合酶链式反应检测血管紧张素转换酶和血管紧张素Ⅱ1型受体(AT1a-R)在S肿瘤组织中的表达。但未检测到AT1b受体和AT2受体。AT1-R主要表达于新生血管内皮细胞，经TCV-116和赖诺普利处理后血管内皮细胞表达减少。这些结果提示，TCV-116可抑制高度依赖AT1a-R阻断剂的肿瘤的血管生成、生长和转移。因此，阻断AT1a-R信号通路可能成为一种有效的肿瘤化学预防新策略。(C)2002年埃尔塞维尔科学公司(美国)。版权所有。
It was reported that angiotensin II stimulates angiogenesis in vivo, and angiotensin-converting enzyme (ACE) inhibitors inhibit angiogenesis. We Found that an AT1-receptor (AT1-R) antagonist, TCV-116, inhibited tumor growth, tumor-associated angiogenesis, and metastasis in a murine model. Tumor growth of Sarcoma 180 (S-180) cells and of fibrosarcoma (NFSA) cells was strongly inhibited by administration of TCV-116 in the diet at a dose of approximately 100 mg/kg/day. This reduction was accompanied with a marked reduction in tumor-associated angiogenesis. The same treatment also reduced the lung metastasis of intravenously injected Lewis lung carcinoma cells. These effects of TCV-116 were equivalent to those of the ACE inhibitor, lisinopril. In S-180 and NFSA tumor tissues, ACE and AT1a receptor (AT1a-R) mRNAs were expressed when assessed with RT-PCR. AT1b receptor and AT2 receptor, however, were not detected. Immunoreactive AT1-R was detected mainly on the neovascularized vascular endothelial cells in which expression was reduced by TCV-116 and lisinopril. These results suggested that TCV-116 inhibits the angiogenesis, growth, and metastasis of tumors highly dependent on AT1a-R blockade. Blockade of AT1a-R signaling may therefore become an effective novel strategy for tumor chemoprevention. (C) 2002 Elsevier Science (USA). All rights reserved.