Requirement for sphingosine 1-phosphate receptor-1 in tumor angiogenesis demonstrated by in vivo RNA interference
Requirement for sphingosine 1-phosphate receptor-1 in tumor angiogenesis demonstrated by in vivo RNA interference
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DOI：
10.1172/jci200422716
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发表时间：
2004-10-01
影响因子：
15.9
通讯作者：
Hla, T
中科院分区：
文献类型：
--
作者：
Chae, SS;Paik, JH;Hla, T
血管生成或新血管的形成对肿瘤的生长和扩散至关重要。这一过程的多个阶段，即迁移、增殖、形态发生和血管稳定，是肿瘤超越扩散限制大小的最佳生长所必需的。鞘氨醇1-磷酸（S1P）受体-1 （S1P(1)）是胚胎发育过程中新生血管稳定所必需的。我们发现S1P(1)的表达在肿瘤血管中被强烈诱导。我们开发了一种多重RNA干扰技术来下调小鼠的S1P(1)。S1P(1)的小干扰RNA （siRNA）特异性地沉默内皮细胞中的同源转录物，并在体外抑制内皮细胞迁移和体内新生血管向皮下植入物Matrigel的生长。在已建立的肿瘤中局部注射S1P(1) siRNA，而不是阴性对照siRNA，可以抑制新生血管上S1P(1)多肽的表达，同时抑制血管稳定和血管生成，从而在体内显著抑制肿瘤生长。这些数据表明，S1P(1)是肿瘤血管生成反应的关键组成部分，并论证了siRNA技术在抗血管生成治疗中的应用。
Angiogenesis, or new blood vessel formation, is critical for the growth and spread of tumors. Multiple phases of this process, namely, migration, proliferation, morphogenesis, and vascular stabilization, are needed for optimal tumor growth beyond a diffusion-limited size. The sphingosine 1-phosphate (S1P) receptor-1 (S1P(1)) is required for stabilization of nascent blood vessels during embryonic development. Here we show that S1P(1) expression is strongly induced in tumor vessels. We developed a multiplex RNA interference technique to downregulate S1P(1) in mice. The small interfering RNA (siRNA) for S1P(1) specifically silenced the cognate transcript in endothelial cells and inhibited endothelial cell migration in vitro and the growth of neovessels into subcutaneous implants of Matrigel in vivo. Local injection of S1P(1) siRNA, but not a negative control siRNA, into established tumors inhibited the expression of S1P(1) polypeptide on neovessels while concomitantly suppressing vascular stabilization and angiogenesis, which resulted in dramatic suppression of tumor growth in vivo. These data suggest that S1P(1) is a critical component of the tumor angiogenic response and argue for the utility of siRNA technology in antiangiogenic therapeutics.