Adrenomedullin antagonist suppresses tumor formation in renal cell carcinoma through inhibitory effects on tumor endothelial cells and endothelial progenitor mobilization.
Adrenomedullin antagonist suppresses tumor formation in renal cell carcinoma through inhibitory effects on tumor endothelial cells and endothelial progenitor mobilization.
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DOI：
10.3892/ijo_00000622
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发表时间：
2010-06
影响因子：
5.2
通讯作者：
K. Tsuchiya;K. Hida;Y. Hida;C. Muraki;N. Ohga;T. Akino;T. Kondo;T. Miseki;K. Nakagawa;M. Shindoh;T. Harabayashi;N. Shinohara;K. Nonomura;Masanobu Kobayashi
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文献类型：
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作者：
K. Tsuchiya;K. Hida;Y. Hida;C. Muraki;N. Ohga;T. Akino;T. Kondo;T. Miseki;K. Nakagawa;M. Shindoh;T. Harabayashi;N. Shinohara;K. Nonomura;Masanobu Kobayashi
肾上腺髓质素(AM)是一种由52个氨基酸组成的多功能多肽。AM有多种作用，并在几种类型的癌细胞中起到生长因子的作用。我们先前的研究表明AM拮抗剂(AMA)抑制小鼠胰腺肿瘤的生长，但其机制尚未阐明。在本研究中，我们构建了AMA表达载体，并将其用于治疗小鼠肾细胞癌。该AMA表达载体显著减少了小鼠肿瘤的生长。此外，AMA治疗的肿瘤微血管密度降低。为了分析AMA对该模型肿瘤血管生成的影响，从RCC移植瘤中分离出肿瘤内皮细胞(TECs)。AM刺激Tec增殖，AMA对Tec增殖有明显抑制作用。AM可诱导TECs迁移，并可被AMA阻断。而正常内皮细胞(NECs)不受AM或AMA的影响。这些结果表明，AMA对TECs有特异性抑制作用，而对NEC无抑制作用，从而抑制肿瘤血管生成。此外，我们还发现AMA抑制了血管内皮生长因子诱导的内皮祖细胞(EPC)的动员进入循环。这些结果表明，AMA可以被认为是一种很好的抗血管生成试剂，选择性地靶向TECs和EPC治疗肾癌。
Adrenomedullin (AM) is a multifunctional 52-amino acid peptide. AM has several effects and acts as a growth factor in several types of cancer cells. Our previous study revealed that an AM antagonist (AMA) suppressed the growth of pancreatic tumors in mice, although its mechanism was not elucidated. In this study, we constructed an AMA expression vector and used it to treat renal cell carcinoma (RCC) in mice. This AMA expression vector significantly reduced tumor growth in mice. In addition, microvessel density was decreased in AMA-treated tumors. To analyze the effect of AMA on tumor angiogenesis in this model, tumor endothelial cells (TECs) were isolated from RCC xenografts. TEC proliferation was stimulated by AM and it was inhibited by AMA significantly. AM induced migration of TECs and it was also blocked by AMA. However, normal ECs (NECs) were not affected by either AM or AMA. These results demonstrate that AMA has inhibitory effects on TECs specifically, not on NEC, thereby inhibiting tumor angiogenesis. Furthermore, we showed that vascular endothelial growth factor-induced mobilization of endothelial progenitor cell (EPC) into circulation was inhibited by AMA. These results suggest that AMA can be considered a good anti-angiogenic reagent that selectively targets TECs and EPC in renal cancer.