Role of host angiotensin II type 1 receptor in tumor angiogenesis and growth.
Role of host angiotensin II type 1 receptor in tumor angiogenesis and growth.
复制标题
DOI：
10.1172/jci16645
复制
发表时间：
2003-07
期刊：
影响因子：
--
通讯作者：
K. Egami;T. Murohara;Toshifumi Shimada;Ken-ichiro Sasaki;Satoshi Shintani;T. Sugaya;M. Ishii;T. Akagi
中科院分区：
文献类型：
--
作者：
K. Egami;T. Murohara;Toshifumi Shimada;Ken-ichiro Sasaki;Satoshi Shintani;T. Sugaya;M. Ishii;T. Akagi
尽管肾素血管紧张素系统(RAS)是血管内稳态的主要调节因子，但RAS在肿瘤血管生成中的作用却鲜为人知。在这里，我们展示了宿主血管紧张素II(ATII)1型(AT1)受体在小鼠移植瘤细胞的血管生成和生长中起重要作用。通过组织毛细血管密度和微血管造影术评估，皮下B16-F1黑色素瘤诱导的血管生成在WT小鼠中显著，但在AT1a受体缺陷(AT1a-/-)小鼠中减少。因此，AT1a-/-小鼠的肿瘤生长速度明显慢于WT小鼠，小鼠存活率高于WT小鼠。用AT1受体的选择性阻断剂TCV-116治疗的WT小鼠的肿瘤生长也减少了。由于β-半乳糖苷酶基因被插入到AT1a-/-小鼠的AT1a基因座上，因此，β-半乳糖苷酶的表达部位代表了AT1a受体在这些突变小鼠中的表达。在移植肿瘤的AT1a-/-小鼠中，β-半乳糖苷酶表达的主要部位是肿瘤周围组织中的巨噬细胞。此外，AT1a-/-小鼠的巨噬细胞数明显少于WT小鼠，双重免疫荧光染色显示这些巨噬细胞强烈表达血管内皮生长因子蛋白。因此，宿主ATII-AT1受体途径支持肿瘤相关巨噬细胞的浸润，从而导致组织中VEGF蛋白水平的升高。因此，宿主ATII-AT1受体通路在体内肿瘤相关血管生成和生长中发挥重要作用。
Although the renin angiotensin system (RAS) is a major regulator of vascular homeostasis, the role of the RAS in tumor angiogenesis is little understood. Here we show that host angiotensin II (ATII) type 1 (AT1) receptor plays an important role in angiogenesis and growth of tumor cells engrafted in mice. Subcutaneous B16-F1 melanoma-induced angiogenesis as assessed by tissue capillary density and microangiography was prominent in WT mice but was reduced in AT1a receptor-deficient (AT1a-/-) mice. Consequently, tumor growth rate was significantly slower, and the mouse survival rate was greater, in AT1a-/- mice than in WT mice. Tumor growth was also reduced in WT mice treated with TCV-116, a selective blocker of AT1 receptor. Because the beta-galactosidase gene was inserted into the AT1a gene locus in AT1a-/- mice, the site of beta-galactosidase expression represents the AT1a receptor expression in these mutant mice. In tumor-implanted AT1a-/- mice, the major site of the beta-galactosidase expression was macrophages in tissues surrounding tumors. Moreover, the number of infiltrated macrophages was significantly lower in AT1a-/- mice than in WT mice, and double-immunofluorescence staining revealed that these macrophages expressed VEGF protein intensively. Therefore, the host ATII-AT1 receptor pathway supports tumor-associated macrophage infiltration, which results in enhanced tissue VEGF protein levels. The host ATII-AT1 receptor pathway thereby plays important roles in tumor-related angiogenesis and growth in vivo.