Angiopoietin-2 Functions as a Tie2 Agonist in Tumor Models, Where It Limits the Effects of VEGF Inhibition
Angiopoietin-2 Functions as a Tie2 Agonist in Tumor Models, Where It Limits the Effects of VEGF Inhibition
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DOI：
10.1158/0008-5472.can-12-2064
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发表时间：
2013-01-01
期刊：
影响因子：
11.2
通讯作者：
Thurston, Gavin
中科院分区：
文献类型：
--
作者：
Daly, Christopher;Eichten, Alexandra;Thurston, Gavin
血管生成素Ang1(ANGPT1)和Ang2(ANGPT2)是一种分泌因子，能与内皮细胞特异性受体酪氨酸激酶Tie2(TEK)结合，调节血管生成。血管紧张素转换酶1激活铁蛋白2促进血管成熟和稳定。相比之下，肿瘤内皮细胞高表达的Ang2被认为可以抑制Tie2的活性，破坏血管的稳定，从而促进血管内皮生长依赖的血管生长。在这里，我们证明了由Ang2特异性抗体(REGN910)引起的对肿瘤异种移植生长的抑制可以通过全身给予Tie2激动剂Ang1而逆转。这些结果表明，Ang2阻断通过降低Tie2的活性来抑制肿瘤的生长，表明Ang2是Tie2的激活剂。REGN910治疗肿瘤导致被Tie2激活抑制的基因表达增加，为REGN910抑制Tie2信号提供了进一步的证据。REGN910与血管内皮生长因子阻滞剂afLibercept的联合治疗比任何一种药物更显著地减少肿瘤血管和肿瘤灌注量，导致更广泛的肿瘤细胞死亡和更有效的抑制肿瘤生长。我们的研究结果表明，Ang2通过激活Tie2对肿瘤内皮细胞起到保护作用，从而限制了血管内皮生长因子抑制的抗血管作用。因此，阻断Ang2可能会增强目前抗血管内皮生长因子药物所提供的临床益处。癌症资源；73(1)；108-18。(C)2012年AACR。
The angiopoietins Ang1 (ANGPT1) and Ang2 (ANGPT2) are secreted factors that bind to the endothelial cell-specific receptor tyrosine kinase Tie2 (TEK) and regulate angiogenesis. Ang1 activates Tie2 to promote blood vessel maturation and stabilization. In contrast, Ang2, which is highly expressed by tumor endothelial cells, is thought to inhibit Tie2 activity and destabilize blood vessels, thereby facilitating VEGF-dependent vessel growth. Here, we show that the inhibition of tumor xenograft growth caused by an Ang2-specific antibody (REGN910) is reversed by systemic administration of the Tie2 agonist Ang1. These results indicate that Ang2 blockade inhibits tumor growth by decreasing Tie2 activity, showing that Ang2 is a Tie2 activator. REGN910 treatment of tumors resulted in increased expression of genes that are repressed by Tie2 activation, providing further evidence that REGN910 inhibits Tie2 signaling. Combination treatment with REGN910 plus the VEGF blocker aflibercept reduced tumor vascularity and tumor perfusion more dramatically than either single agent, resulting in more extensive tumor cell death and more potent inhibition of tumor growth. Challenging the prevailing model of Ang2 as a destabilizing factor, our findings indicate that Ang2 plays a protective role in tumor endothelial cells by activating Tie2, thereby limiting the antivascular effects of VEGF inhibition. Thus, blockade of Ang2 might enhance the clinical benefits currently provided by anti-VEGF agents. Cancer Res; 73(1); 108-18. (C) 2012 AACR.