Destruction of tumor vasculature and abated tumor growth upon VEGF blockade is driven by proapoptotic protein Bim in endothelial cells.
Destruction of tumor vasculature and abated tumor growth upon VEGF blockade is driven by proapoptotic protein Bim in endothelial cells.
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DOI：
10.1084/jem.20100951
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发表时间：
2011-07-04
期刊：
影响因子：
--
通讯作者：
Strasser A
中科院分区：
文献类型：
--
作者：
Naik E;O'Reilly LA;Asselin-Labat ML;Merino D;Lin A;Cook M;Coultas L;Bouillet P;Adams JM;Strasser A
VEGF剥夺诱导了肿瘤内皮细胞中Bim的表达，而Bim是抗VEGF驱动的内皮细胞死亡和肿瘤缩小所必需的。对于恶性生长，实体癌必须通过产生血管内皮生长因子（VEGF-A）来刺激新血管的形成，这是肿瘤相关血管存活所必需的。阻断VEGF-A信号的新型抗癌药物可优先触发肿瘤内内皮细胞（EC）凋亡和血管退化，但内皮细胞是如何死亡的尚不清楚。在这项研究中，我们证明了VEGF-A剥夺，无论是由药物诱导的肿瘤缩小还是直接阻断VEGF-A，都可以上调内皮细胞中促凋亡的BH3 (Bcl-2同源3)-仅Bcl-2家族成员Bim。重要的是，VEGF-A拮抗剂的肿瘤生长抑制活性需要bim诱导的内皮细胞凋亡。这些发现揭示了VEGF-A阻断诱导EC细胞凋亡和损害肿瘤生长的机制。他们还表明，模仿BH3-only蛋白的药物不仅可以直接杀死肿瘤细胞，还可以通过消融肿瘤血管间接杀死肿瘤细胞。
VEGF deprivation induces Bim expression in tumor endothelial cells, and Bim is needed for anti-VEGF–driven endothelial cell death and tumor shrinkage. For malignant growth, solid cancers must stimulate the formation of new blood vessels by producing vascular endothelial growth factor (VEGF-A), which is required for the survival of tumor-associated vessels. Novel anticancer agents that block VEGF-A signaling trigger endothelial cell (EC) apoptosis and vascular regression preferentially within tumors, but how the ECs die is not understood. In this study, we demonstrate that VEGF-A deprivation, provoked either by drug-induced tumor shrinkage or direct VEGF-A blockade, up-regulates the proapoptotic BH3 (Bcl-2 homology 3)-only Bcl-2 family member Bim in ECs. Importantly, the tumor growth inhibitory activity of a VEGF-A antagonist required Bim-induced apoptosis of ECs. These findings thus reveal the mechanism by which VEGF-A blockade induces EC apoptosis and impairs tumor growth. They also indicate that drugs mimicking BH3-only proteins may be exploited to kill tumor cells not only directly but also indirectly by ablating the tumor vasculature.
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