Potent VEGF blockade causes regression of coopted vessels in a model of neuroblastoma
Potent VEGF blockade causes regression of coopted vessels in a model of neuroblastoma
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DOI：
10.1073/pnas.172398399
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发表时间：
2002-08-20
影响因子：
11.1
通讯作者：
Yamashiro, DJ
中科院分区：
文献类型：
--
作者：
Kim, ES;Serur, A;Yamashiro, DJ
血管内皮生长因子（VEGF）在肿瘤血管生成中起关键作用。我们比较了不同特异性的VEGF抑制剂在神经母细胞瘤异种移植模型中的作用。将培养的人神经母细胞瘤NGP-GFP细胞肾内植入裸鼠体内。检测了三种抗VEGF药物：基于抗人VEGF（165）RNA的氟嘧啶适体;单克隆抗人VEGF抗体;和VEGF-Trap，一种基于VEGFR-1和VEGFR-2融合至IgG 1 Fc片段的复合诱饵受体。观察到广泛的功效，其中高剂量VEGF-Trap引起肿瘤生长的最大抑制（与对照相比为81%）。我们检查了肿瘤血管生成，发现在肿瘤形成的早期，宿主血管发生了共选择。我们假设，这种增选的血管系统作为血液供应的来源，在肿瘤生长的初始阶段。随后，对照肿瘤经历血管网络的蓬勃生长和重塑，这导致增配血管的消失。然而，如果VEGF功能被阻断，宿主血管的共选择可能持续。因此，持续的协同作用可能代表了一种新的机制，通过这种机制，神经母细胞瘤可以部分逃避抗血管生成治疗，并可能解释为什么实验性神经母细胞瘤比肾母细胞瘤的平行模型对VEGF阻断不那么敏感。然而，更有效的VEGF阻断，如通过高剂量的VEGF-Trap实现的，可导致共同选择的血管结构的消退。这些结果表明，宿主脉管系统的共选择是肿瘤形成的早期事件，并且这种效应的持续性与VEGF活性的阻断程度有关。
Vascular endothelial growth factor (VEGF) plays a key role in human tumor angiogenesis. We compared the effects of inhibitors of VEGF with different specificities in a xenograft model of neuroblastoma. Cultured human neuroblastoma NGP-GFP cells were implanted intrarenally in nude mice. Three anti-VEGF agents were tested: an anti-human VEGF(165) RNA-based fluoropyrimidine aptamer; a monoclonal anti-human VEGF antibody; and VEGF-Trap, a composite decoy receptor based on VEGFR-1 and VEGFR-2 fused to an Fc segment of IgG1. A wide range of efficacy was observed, with high-dose VEGF-Trap causing the greatest inhibition of tumor growth (81% compared with controls). We examined tumor angiogenesis and found that early in tumor formation, cooption of host vasculature occurs. We postulate that this coopted vasculature serves as a source of blood supply during the initial phase of tumor growth. Subsequently, control tumors undergo vigorous growth and remodeling of vascular networks, which results in disappearance of the coopted vessels. However, if VEGF function is blocked, cooption of host vessels may persist. Persistent cooption, therefore, may represent a novel mechanism by which neuroblastoma can partly evade antiangiogenic therapy and may explain why experimental neuroblastoma is less susceptible to VEGF blockade than a parallel model of Wilms tumor. However, more effective VEGF blockade, as achieved by high doses of VEGF-Trap, can lead to regression of coopted vascular structures. These results demonstrate that cooption of host vasculature is an early event in tumor formation, and that persistence of this effect is related to the degree of blockade of VEGF activity.