Genetic Deletion of Vascular Endothelial Growth Factor Receptor 2 in Endothelial Cells Leads to Immediate Disruption of Tumor Vessels and Aggravation of Hypoxia.
Genetic Deletion of Vascular Endothelial Growth Factor Receptor 2 in Endothelial Cells Leads to Immediate Disruption of Tumor Vessels and Aggravation of Hypoxia.
复制标题
内皮细胞中血管内皮生长因子受体 2 的基因缺失会导致肿瘤血管立即破坏并加剧缺氧。
DOI：
10.1016/j.ajpath.2021.11.003
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
*Tai-Nagara I.
中科院分区：
文献类型：
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作者：
Kido Y;Ando T;Iga T;Ema M;*Kubota Y;*Tai-Nagara I.
血管内皮生长因子（VEGF）阻断剂在临床上广泛用于靶向各种类型的人类癌症。尽管VEGF阻断剂发挥显著的肿瘤抑制作用，但治疗效果可能有限。此外，越来越多的证据表明，VEGF不仅作用于内皮细胞，而且作用于各种非内皮细胞，包括肿瘤和免疫细胞，这表明需要使用特定的遗传小鼠模型重新审视VEGF对内皮细胞的真正作用。在本文中，使用了缺乏VEGF受体2（Vegfr 2）（VEGF的主要信号转导子）的他莫昔芬诱导的内皮特异性敲除小鼠。内皮细胞Vegfr 2信号传导停止导致的初始事件是血管截断和碎裂，而不是异常血管的成熟。尽管内皮细胞Vegfr 2的缺失抑制了肿瘤内出血，但它增强了肿瘤细胞中的缺氧，减少了浸润性细胞毒性T细胞的数量，这表明肿瘤内血流显著减少。在各种组织中，内皮细胞Vegfr 2的缺失诱导肠绒毛中健康毛细血管的消退，证实肠穿孔，这是人体VEGF阻断的最常见不良反应之一。总体而言，数据表明，VEGF阻断剂对肿瘤血管的一些已知作用是由VEGF信号传导的部分停止或对非内皮细胞的作用引起的。这些结果增加了对抗血管生成治疗机制的理解。
Vascular endothelial growth factor (VEGF) blockers are used widely in clinics to target various types of human cancer. Although VEGF blockers exert marked tumor suppressive effects, the therapeutic effects can be limited. Moreover, accumulating evidence shows that VEGF acts not just on endothelial cells but also on various nonendothelial cells, including tumor and immune cells, suggesting a need to revisit the bona fide action of VEGF on endothelial cells using specific genetic mouse models. Herein, tamoxifen-inducible endothelial-specific knockout mice lacking VEGF receptor 2 (Vegfr2), the major signal transducer for VEGF, were used. The initial event resulting from cessation of endothelial Vegfr2 signaling was vascular truncation and fragmentation, rather than maturation of abnormalized vessels. Although deletion of endothelialVegfr2suppressed intratumor hemorrhage, it enhanced hypoxia in tumor cells and reduced the number of infiltrating cytotoxic T cells, suggesting a profound reduction in intratumor blood flow. In various tissues, deletion of endothelialVegfr2induced regression of healthy capillaries in intestinal villi, substantiating intestinal perforation, which is one of the most common adverse effects of VEGF blockade in humans. Overall, the data suggest that some of the known effects of VEGF blockers on tumor vessels are caused by partial cessation of VEGF signaling, or by actions on nonendothelial cells. The results increase the understanding of the mechanisms underlying anti-angiogenic therapy.