A class of extracellular vesicles from breast cancer cells activates VEGF receptors and tumour angiogenesis.
A class of extracellular vesicles from breast cancer cells activates VEGF receptors and tumour angiogenesis.
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DOI：
10.1038/ncomms14450
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发表时间：
2017-02-16
影响因子：
16.6
通讯作者：
Cerione RA
中科院分区：
文献类型：
--
作者：
Feng Q;Zhang C;Lum D;Druso JE;Blank B;Wilson KF;Welm A;Antonyak MA;Cerione RA
非经典的分泌囊泡，统称为细胞外囊泡（EV），涉及癌细胞存活和转移的不同方面。在这里，我们描述了一类特定的EV，称为微泡（MV），如何通过独特的90 kDa形式的VEGF（VEGF 90 K）激活VEGF受体和肿瘤血管生成。我们表明，VEGF90 K是由VEGF165的交联产生的，由酶组织转氨酶催化，并通过其与分子伴侣Hsp90的相互作用与MV相关联。我们进一步证明MV相关VEGF 90 K对贝伐单抗的亲和力减弱，导致贝伐单抗在阻断MV依赖性VEGF受体活化方面无效。然而，用Hsp90抑制剂治疗从MV释放VEGF 90 K，恢复VEGF 90 K对贝伐单抗的敏感性。这些发现揭示了癌细胞衍生的MV影响肿瘤微环境的新机制，并强调了在考虑药物治疗策略时认识其独特性质的重要性。细胞外囊泡（EV）含有VEGF，可促进肿瘤血管生成，尽管其机制尚不清楚。在这里，作者发现一种对贝伐单抗耐药但对HSP90抑制剂敏感的VEGF（VEGF90K）通过与HSP90的相互作用与EV相关。
Non-classical secretory vesicles, collectively referred to as extracellular vesicles (EVs), have been implicated in different aspects of cancer cell survival and metastasis. Here, we describe how a specific class of EVs, called microvesicles (MVs), activates VEGF receptors and tumour angiogenesis through a unique 90 kDa form of VEGF (VEGF90K). We show that VEGF90K is generated by the crosslinking of VEGF165, catalysed by the enzyme tissue transglutaminase, and associates with MVs through its interaction with the chaperone Hsp90. We further demonstrate that MV-associated VEGF90K has a weakened affinity for Bevacizumab, causing Bevacizumab to be ineffective in blocking MV-dependent VEGF receptor activation. However, treatment with an Hsp90 inhibitor releases VEGF90K from MVs, restoring the sensitivity of VEGF90K to Bevacizumab. These findings reveal a novel mechanism by which cancer cell-derived MVs influence the tumour microenvironment and highlight the importance of recognizing their unique properties when considering drug treatment strategies. Extracellular vesicles (EVs) contain VEGF and can contribute to tumour angiogenesis, although the mechanism remains unclear. Here, the authors find that a form of VEGF (VEGF90K) resistant to Bevacizumab but sensitive to HSP90 inhibitors, associates with EVs through its interaction with Hsp90.