Tie1 deletion inhibits tumor growth and improves angiopoietin antagonist therapy
Tie1 deletion inhibits tumor growth and improves angiopoietin antagonist therapy
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DOI：
10.1172/jci68897
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发表时间：
2014-02-01
影响因子：
15.9
通讯作者：
Alitalo, Kari
中科院分区：
文献类型：
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作者：
D'Amico, Gabriela;Korhonen, Emilia A.;Alitalo, Kari
内皮Tie1受体无配体，但与Tie2受体相互作用产生血管生成素（Angpt）。Angpt2在肿瘤血管中表达，其阻断抑制肿瘤血管生成。我们发现，成年小鼠内皮中Tie1的缺失通过降低肿瘤血管中内皮细胞的存活来抑制肿瘤血管的生成和生长，而不影响正常的血管系统。用VEGF或VEGFR-2阻断抗体治疗类似地减少肿瘤血管生成和生长；然而，同时靶向Tie1和VEGF/VEGFR-2未获得加性抑制。相反，用可溶形式的Tie2细胞外结构域（可阻断Angpt活性）治疗tie1缺陷小鼠，可导致肿瘤生长的加性抑制。值得注意的是，Tie1缺失减少了新生血管的生成，增加了出生后视网膜血管中Notch通路的活性，而在缺乏Tie1的情况下，Notch的药理抑制促进了视网膜血管增生。此外，当给予tie1缺陷幼鼠Angpt2阻断抗体时，观察到视网膜血管前沿迁移的实质性加性抑制。因此，Tie1调节肿瘤血管生成、出生后新生血管生成和内皮细胞存活，这些都是由VEGF、Angpt和Notch信号控制的。我们的研究结果表明，结合Angpt/Tie2靶向Tie1有可能改善抗血管生成治疗。
The endothelial Tie1 receptor is ligand-less, but interacts with the Tie2 receptor for angiopoietins (Angpt). Angpt2 is expressed in tumor blood vessels, and its blockade inhibits tumor angiogenesis. Here we found that Tie1 deletion from the endothelium of adult mice inhibits tumor angiogenesis and growth by decreasing endothelial cell survival in tumor vessels, without affecting normal vasculature. Treatment with VEGF or VEGFR-2 blocking antibodies similarly reduced tumor angiogenesis and growth; however, no additive inhibition was obtained by targeting both Tie1 and VEGF/VEGFR-2. In contrast, treatment of Tie1-deficient mice with a soluble form of the extracellular domain of Tie2, which blocks Angpt activity, resulted in additive inhibition of tumor growth. Notably, Tie1 deletion decreased sprouting angiogenesis and increased Notch pathway activity in the postnatal retinal vasculature, while pharmacological Notch suppression in the absence of Tie1 promoted retinal hypervasularization. Moreover, substantial additive inhibition of the retinal vascular front migration was observed when Angpt2 blocking antibodies were administered to Tie1-deficient pups. Thus, Tie1 regulates tumor angiogenesis, postnatal sprouting angiogenesis, and endothelial cell survival, which are controlled by VEGF, Angpt, and Notch signals. Our results suggest that targeting Tie1 in combination with Angpt/Tie2 has the potential to improve antiangiogenic therapy.