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
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DOI：
10.1038/labinvest.3700504
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发表时间：
2007-02-01
影响因子：
5
通讯作者：
Umemura, Satoshi
中科院分区：
文献类型：
--
作者：
Imai, Nozomi;Hashimoto, Tatsuo;Umemura, Satoshi
血管紧张素II （Angiotensin II, All）是一种多功能生物活性肽，宿主肾素-血管紧张素系统（renin-angiotensin system， RAS）与肿瘤生长密切相关。最近的报道描述了All是一种促血管生成生长因子，血管紧张素11 1型（AT1）受体拮抗剂可减少肿瘤生长和肿瘤相关的血管生成。在本文中，我们利用表达AT1受体的小鼠Lewis肺癌（LLC）细胞和AT1a受体基因缺陷（AT1a-/-）小鼠研究了AT1受体信号在癌症进展中的参与。当将LLC细胞皮下植入野生型（WT）小鼠时，在诱导血管内皮生长因子（VEGF） a的情况下，已形成的肿瘤显示出强烈的血管生成。与WT小鼠相比，AT1a-/-小鼠的肿瘤生长和肿瘤相关血管生成减少，VEGFa表达降低。在AT1a-/-小鼠中，给予AT1受体拮抗剂TCV-116，显示肿瘤生长、肿瘤相关血管生成和VEGFa表达进一步降低。在体外研究中，All可显著增加LLC细胞中VEGFa mRNA的表达和VEGFa蛋白的产生，而AT1受体拮抗剂CV-11974可抵消这一作用。虽然我们也研究了其他血管生成因子如血管生成素-1、血管生成素-2、表皮生长因子和VEGF受体2 mRNA在肿瘤组织中的表达，但在这些血管生成因子中，VEGF的表达与肿瘤大小的相关性最大。宿主和肿瘤组织中AT1受体信号诱导VEGFa是肿瘤生长和肿瘤相关血管生成的关键调控因子之一。综上所述，我们发现肿瘤组织RAS和宿主组织RAS在肿瘤生长中具有重要作用。AT1受体信号阻断可能是治疗癌症的一个新的有效靶点。
Angiotensin II (All) is a multifunctional bioactive peptide, and host renin-angiotensin system (RAS) is closely associated with tumor growth. Recent reports have described that All is a proangiogenic growth factor, and that Angiotensin 11 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 AT1 a 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 All, 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.