Tumor-surrogate blood vessel subtypes exhibit differential susceptibility to anti-VEGF therapy.
Tumor-surrogate blood vessel subtypes exhibit differential susceptibility to anti-VEGF therapy.
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DOI：
10.1158/0008-5472.can-11-1693
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发表时间：
2011-11-15
期刊：
影响因子：
11.2
通讯作者：
Dvorak HF
中科院分区：
文献类型：
--
作者：
Sitohy B;Nagy JA;Jaminet SC;Dvorak HF
针对 VEGF 或其受体的抗血管治疗在肿瘤血管生长的早期阶段施用时是成功的，但在后期施用时效果较差。肿瘤血管具有异质性，因此血管亚群对肿瘤细胞分泌的 VEGF 的需求以及对抗 VEGF/VEGFR 治疗的敏感性可能有所不同。人类癌症包含几种不同的血管类型，包括母血管 (MV)、肾小球微血管增生 (GMP)、血管畸形 (VM)、供血动脉 (FA) 和引流静脉 (DV)，所有这些都可以在没有肿瘤细胞的情况下使用 VEGF-A164 表达载体在小鼠中产生。在这项研究中，我们研究了每种血管类型对使用 aflibercept ® (VEGF Trap)（一种 VEGF-A164 的有效抑制剂）进行抗 VEGF 治疗的敏感性。在注射表达重组 VEGF-A164 的腺病毒之前或之后不久进行 VEGF Trap 治疗可以预防或消退无肿瘤的新血管系统，但如果稍后开始，效果会逐渐降低。早期形成的 MV 和 GMP 中的内皮细胞表达高水平的 VEGFR-2，非常容易被 VEGF Trap 阻断。相比之下，表达低水平 VEGFR-2 的晚期形成的 VM、FA 和 DV 在很大程度上具有耐药性。总之，我们的研究结果定义了不同血管亚型对抗 VEGF 治疗的敏感性，为抗 VEGF-A/VEGFR 治疗人类癌症的有效性有限提供了可能的解释，这些癌症通常在发现前数月至数年存在，并且主要由晚期形成的血管组成。
Anti-vascular therapy directed against VEGF or its receptors has been successful when administered at early stages of tumor vessel growth, but is less effective when administered later. Tumor blood vessels are heterogeneous, so vessel subpopulations may differ in their requirements for tumor cell-secreted VEGF and in their susceptibility to anti-VEGF/VEGFR therapy. Human cancers contain several distinct blood vessel types, including mother vessels (MV), glomeruloid microvascular proliferations (GMP), vascular malformations (VM), feeding arteries (FA) and draining veins (DV), all of which can be generated in mice in the absence of tumor cells using expression vectors for VEGF-A164. In this study, we investigated the sensitivity of each of these vessel types to anti-VEGF therapy with aflibercept ® (VEGF Trap), a potent inhibitor of VEGF-A164. Administering VEGF Trap treatment before or shortly after injection of a recombinant VEGF-A164 expressing adenovirus could prevent or regress tumor-free neovasculature, but it was progressively less effective if initiated at later times. Early-forming MVs and GMPs in which the lining endothelial cells expressed high levels of VEGFR-2 were highly susceptible to blockade by VEGF Trap. In contrast, late-forming VMs, FAs, and DVs that expressed low levels of VEGFR-2 were largely resistant. Together, our findings define the susceptibility of different blood vessel subtypes to anti-VEGF therapy, offering a possible explanation for the limited effectiveness of anti-VEGF-A/VEGFR treatment of human cancers, which are typically present for months to years before discovery and are largely populated by late-forming blood vessels.