Angiopoietin-1/Tie-2 activation contributes to vascular survival and tumor growth during VEGF blockade
Angiopoietin-1/Tie-2 activation contributes to vascular survival and tumor growth during VEGF blockade
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DOI：
10.3892/ijo_00000131
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发表时间：
2009-01-01
影响因子：
5.2
通讯作者：
Kandel, Jessica J.
中科院分区：
文献类型：
--
作者：
Huang, Jianzhong;Bae, Jae-O;Kandel, Jessica J.
2004年FDA批准抗血管内皮生长因子（VEGF）抗体贝伐单抗，反映了这种血管靶向策略在延长晚期癌症患者生存期方面的成功。然而，与先前的报道一致，实验性肿瘤可以生长或复发。在VEGF阻断期间，很明显，许多接受VEGF抑制剂治疗的患者最终会发展为进行性疾病。先前的研究表明，肿瘤中VEGF信号的破坏会诱导存活血管的重塑，并将血管生成素-1 （ang1）的表达增加与这一过程联系起来。然而，在不同的肿瘤中，Ang-1的过表达产生了不同的结果，在一些系统中限制血管生成，而在另一些系统中促进血管生成。这些数据提出了Ang-1/Tie-2的影响可能与环境有关的可能性。在我们的模型中，治疗前Ang1构建体（Ang1*）的表达没有显著改变肿瘤生长，尽管血管表现出与Tie-2信号通路增加一致的变化。然而，在抑制VEGF的过程中，Ang1*的过度表达和工程Ang1激动剂（Bow-Ang1）的施用都显著地保护了肿瘤和血管系统免受退化。在这种情况下，Ang-1/Tie-2的激活限制了肿瘤缺氧，增加了血管直径，促进了壁细胞的募集。因此，这些研究支持了一个模型，在这个模型中，当vegf依赖性的血管系统受到压力时，Tie-2的激活对肿瘤和血管存活很重要。了解这种对这种有效治疗形式的适应机制对于设计最佳利用这种方法的方案可能很重要。
Approval of the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab by the FDA in 2004 reflected the success of this vascular targeting strategy in extending survival in patients with advanced cancers. However, consistent with previous reports that experimental tumors can grow or recur. during VEGF blockade, it has become clear that many patients treated with VEGF inhibitors will ultimately develop progressive disease. Previous studies have shown that disruption of VEGF signaling in tumors induces remodeling in surviving vessels, and link increased expression of angiopoietin-1 (Ang-1) with this process. However, over -expression of Ang-1 in different tumors has yielded divergent results, restricting angiogenesis in some systems while promoting it in others. These data raise the possibility that effects of Ang-1/Tie-2 may be context-dependent. Expression of an Ang-1 construct (Ang1*) did not significantly change tumor growth in our model prior to treatment, although vessels exhibited changes consistent with increased Tie-2 signaling. During inhibition of VEGF, however, both over-expression of Ang1* and administration of an engineered Ang-1 agonist (Bow-Ang1) strikingly protected tumors and vasculature from regression. In this context, Ang-1/Tie-2 activation limited tumor hypoxia, increased vessel caliber, and promoted recruitment of mural cells. Thus, these studies Support a model in which activation of Tie-2 is important for tumor and vessel survival when VEGF-dependent vasculature is stressed. Understanding such mechanisms of adaptation to this validated form of therapy may be important in designing regimens that make the best use of this approach.