Angiotensin II promotes pulmonary metastasis of melanoma through the activation of adhesion molecules in vascular endothelial cells
Angiotensin II promotes pulmonary metastasis of melanoma through the activation of adhesion molecules in vascular endothelial cells
复制标题
DOI：
10.1016/j.bcp.2018.04.012
复制
发表时间：
2018-08-01
影响因子：
5.8
通讯作者：
Kangawa, Kenji
中科院分区：
文献类型：
--
作者：
Ishikane, Shin;Hosoda, Hiroshi;Kangawa, Kenji
高血压被认为是肿瘤进展的重要因素之一，在肿瘤患者中常伴有高血压。肾素-血管紧张素系统（RAS）在血压调节中起重要作用，血管紧张素II（Ang II）是已知的与RAS相关的升压肽。据报道，血管紧张素II可加速癌细胞的进展和转移。然而，其确切机制尚未完全了解。在这项研究中，我们试图阐明血管紧张素II加剧小鼠黑色素瘤细胞的血行转移的机制，集中在血管内皮细胞的粘附途径。为此，将不表达Ang II 1型受体（AT 1 R）的B16/F10小鼠黑素瘤细胞静脉内注射到C57 BL/6小鼠中。细胞注射后两周，Ang II治疗组（1 μ g/kg/min）的肺转移集落数量显著高于赋形剂治疗组。AT 1 R阻断剂缬沙坦（40 mg/ kg/天），而不是钙通道阻断剂Ketamine（5或10 mg/kg/天），显著抑制了Ang II的作用。在内皮特异性Agtrla基因敲除小鼠中，血管紧张素II介导的黑色素瘤细胞肺转移的加速作用显著减弱。血管紧张素Ⅱ治疗显着增加E-选择素mRNA表达的血管内皮细胞收集从肺组织，从而促进黑色素瘤细胞粘附到血管内皮。用抗E选择素抗体（20 mg/kg）治疗也抑制了血管紧张素II加速的黑色素瘤细胞肺转移。总之，血管紧张素II治疗通过促进E-选择素介导的癌细胞与血管内皮细胞的粘附而加剧血行性癌转移。
Hypertension is considered as one of the cancer progressive factors, and often found comorbidity in cancer patients. Renin-angiotensin system (RAS) plays an important role in the regulation of blood pressure, and angiotensin II (Ang II) is well known pressor peptide associated with RAS. Ang II has been reported to accelerate progression and metastasis of cancer cells. However, its precise mechanisms have not been fully understood. In this study, we sought to elucidate the mechanisms by which Ang II exacerbates hematogenous metastasis in mouse melanoma cells, focusing the adhesion pathway in vascular endothelial cells. For this purpose, B16/F10 mouse melanoma cells, which do not express the Ang II type 1 receptor (AT1R), were intravenously injected into C57BL/6 mice. Two weeks after cell injection, the number of lung metastatic colonies was significantly higher in the Ang II-treated group (1 mu g/kg/min) than in the vehicle-treated group. The AT1R blocker valsartan (40 mg/ kg/day), but not the calcium channel blocker amlodipine (5 or lO mg/kg/day), significantly suppressed the effect of Ang II. In endothelium-specific Agtrla knockout mice, Ang II-mediated acceleration of lung metastases of melanoma cells was significantly diminished. Ang II treatment significantly increased E-selectin mRNA expression in vascular endothelial cells collected from lung tissues, and thus promoted adherence of melanoma cells to the vascular endothelium. Ang II-accelerated lung metastases of melanoma cells were also suppressed by treatment with anti-E selectin antibody (20 mg/kg). Taken together, Ang II-treatment exacerbates hematogenous cancer metastasis by promoting E-selectin-mediated adhesion of cancer cells to vascular endothelial cells.