Inhibition of vascular endothelial growth factor (VEGF) signaling in cancer causes loss of endothelial fenestrations, regression of tumor vessels, and appearance of basement membrane ghosts
Inhibition of vascular endothelial growth factor (VEGF) signaling in cancer causes loss of endothelial fenestrations, regression of tumor vessels, and appearance of basement membrane ghosts
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DOI：
10.1016/s0002-9440(10)63273-7
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发表时间：
2004-07-01
影响因子：
6
通讯作者：
McDonald, DM
中科院分区：
文献类型：
--
作者：
Inai, T;Mancuso, M;McDonald, DM
血管生成抑制剂作为癌症治疗剂越来越受到关注，但人们对这些抑制剂对肿瘤血管的细胞作用知之甚少。我们试图确定两种抑制血管内皮生长因子 (VEGF) 信号传导的药物 AG013736 和 VEGF-Trap 是否仅仅阻止血管生成或导致现有肿瘤血管消退。在这里，我们报告说，使用这些抑制剂进行治疗会导致 RIP-Tag2 转基因小鼠的自发性胰岛细胞肿瘤和皮下植入的 Lewis 肺癌的内皮细胞、周细胞和血管基底膜发生强烈的早期变化。引人注目的是，在 24 小时内，RIP-Tag2 肿瘤中的内皮开窗消失，血管萌芽受到抑制，一些血管通畅和血流停止。 7 天时，血管密度下降超过 70%，存活内皮细胞中 VEGFR-2 和 VEGFR-3 表达减少。刘易斯肺肿瘤中的血管缺乏内皮开窗，显示出较少的消退。在这两种肿瘤中，周细胞的退化程度与内皮细胞不同，并且存活肿瘤血管上的周细胞获得了更正常的表型。内皮细胞退化后，血管基底膜仍然存在，为预处理血管数量和位置提供了幽灵般的记录，并为血管再生提供了潜在的支架。观察到的有效抗血管作用证明 VEGF 信号抑制剂的作用不仅仅是阻止血管生成。 RIP-Tag2 肿瘤中内皮开窗的早期丧失是血管表型可能预示对这些抑制剂异常敏感性的线索。
Angiogenesis inhibitors are receiving increased attention as cancer therapeutics, but little is known of the cellular effects of these inhibitors on tumor vessels. We sought to determine whether two agents, AG013736 and VEGF-Trap, that inhibit vascular endothelial growth factor (VEGF) signaling, merely stop angiogenesis or cause regression of existing tumor vessels. Here, we report that treatment with these inhibitors caused robust and early changes in endothelial cells, pericytes, and basement membrane of vessels in spontaneous islet-cell tumors of RIP-Tag2 transgenic mice and in subcutaneously implanted Lewis lung carcinomas. Strikingly, within 24 hours, endothelial fenestrations in RIP-Tag2 tumors disappeared, vascular sprouting was suppressed, and patency and blood flow ceased in some vessels. By 7 days, vascular density decreased more than 70%, and VEGFR-2 and VEGFR-3 expression was reduced in surviving endothelial cells. Vessels in Lewis lung tumors, which lacked endothelial fenestrations, showed less regression. in both tumors, pericytes did not degenerate to the same extent as endothelial cells, and those on surviving tumor vessels acquired a more normal phenotype. Vascular basement membrane persisted after endothelial cells degenerated, providing a ghost-like record of pretreatment vessel number and location and a potential scaffold for vessel regrowth. The potent anti-vascular action observed is evidence that VEGF signaling inhibitors do more than stop angiogenesis. Early loss of endothelial fenestrations in RIP-Tag2 tumors is a clue that vessel phenotype may be predictive of exceptional sensitivity to these inhibitors.