Role of Angiopoietin-2 in Adaptive Tumor Resistance to VEGF Signaling Blockade
Role of Angiopoietin-2 in Adaptive Tumor Resistance to VEGF Signaling Blockade
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DOI：
10.1016/j.celrep.2014.06.059
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发表时间：
2014-08-07
期刊：
影响因子：
8.8
通讯作者：
De Palma, Michele
中科院分区：
文献类型：
--
作者：
Rigamonti, Nicolo;Kadioglu, Ece;De Palma, Michele
血管生成素-2（Angiopoietin-2，ANG 2/ANGPT 2）是一种环境依赖性TIE 2受体激动剂/拮抗剂和促血管生成因子。尽管ANG 2中和通过血管内皮生长因子（VEGF）-A信号传导阻断改善肿瘤血管生成和生长抑制，但这种治疗益处的机制基础仍然探索不足。我们采用晚期RIP 1-Tag 2胰腺神经内分泌肿瘤（PNTR）和MMTV-PyMT乳腺腺癌，这些肿瘤对VEGF受体2（VEGFR 2）阻断产生耐药性。我们发现，VEGFR 2抑制上调ANG 2和血管TIE 2，并增强了PNIPs中表达TIE 2的巨噬细胞的浸润。双重ANG 2/VEGFR 2阻断抑制大多数PNAR中的血管再生和进展，而它在乳腺肿瘤中仅具有较小的累加效应，其在VEGFR 2抑制后不上调ANG 2。ANG 2/VEGFR 2阻断并没有引起PNET侵袭和转移的增加，尽管它加剧了肿瘤缺氧和造血细胞浸润。这些发现表明，逃避性肿瘤抗VEGFA治疗的耐药性可能涉及ANG 2-TIE 2信号传导的适应性加强，这可以通过ANG 2中和来逆转。
Angiopoietin-2 (ANG2/ANGPT2) is a context-dependent TIE2 receptor agonist/antagonist and proangiogenic factor. Although ANG2 neutralization improves tumor angiogenesis and growth inhibition by vascular endothelial growth factor (VEGF)-A signaling blockade, the mechanistic underpinnings of such therapeutic benefits remain poorly explored. We employed late-stage RIP1-Tag2 pancreatic neuroendocrine tumors (PNETs) and MMTV-PyMT mammary adenocarcinomas, which develop resistance to VEGF receptor 2 (VEGFR2) blockade. We found that VEGFR2 inhibition upregulated ANG2 and vascular TIE2 and enhanced infiltration by TIE2-expressing macrophages in the PNETs. Dual ANG2/VEGFR2 blockade suppressed revascularization and progression in most of the PNETs, whereas it had only minor additive effects in the mammary tumors, which did not upregulate ANG2 upon VEGFR2 inhibition. ANG2/VEGFR2 blockade did not elicit increased PNET invasion and metastasis, although it exacerbated tumor hypoxia and hematopoietic cell infiltration. These findings suggest that evasive tumor resistance to anti-VEGFA therapy may involve the adaptive enforcement of ANG2-TIE2 signaling, which can be reversed by ANG2 neutralization.