Hypoxia triggers a proangiogenic pathway involving cancer cell microvesicles and PAR-2-mediated heparin-binding EGF signaling in endothelial cells
Hypoxia triggers a proangiogenic pathway involving cancer cell microvesicles and PAR-2-mediated heparin-binding EGF signaling in endothelial cells
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DOI：
10.1073/pnas.1104261108
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发表时间：
2011-08-09
影响因子：
11.1
通讯作者：
Belting, Mattias
中科院分区：
文献类型：
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作者：
Svensson, Katrin J.;Kucharzewska, Paulina;Belting, Mattias
高度恶性肿瘤，如胶质母细胞瘤，以缺氧、内皮细胞（EC）增生和高凝为特征。然而，在肿瘤发展过程中，这些肿瘤微环境现象如何在分子水平上联系起来仍然不清楚。在这里，我们提供的证据表明，缺氧上调了ECs中蛋白酶激活受体2 (PAR-2)，即凝固依赖信号的g蛋白偶联受体。缺氧诱导PAR-2可引起血管生成EC表型，并特异性上调肝素结合egf样生长因子（HB-EGF）。通过抗体中和或肝素治疗抑制HB-EGF可有效抵消par -2介导的缺氧ECs活化。我们发现，par -2依赖性HB-EGF诱导与ERK1/2磷酸化增加有关，抑制ERK1/2磷酸化可减弱par -2依赖性HB-EGF诱导和EC激活。组织因子（TF），即凝固依赖性PAR信号的主要发起者，在几种类型的癌细胞中被缺氧诱导，包括胶质母细胞瘤；然而，即使在长时间缺氧的情况下，内皮细胞中也检测不到TF，这就排除了细胞通过TF自主激活PAR-2的可能性。有趣的是，缺氧癌细胞释放了大量的TF，这主要与具有外泌体样特征的分泌微泡有关。来自胶质母细胞瘤细胞的囊泡被发现以旁分泌方式触发TF/ viia依赖性缺氧ec的激活。我们提供了缺氧诱导的信号轴将癌细胞中的凝血激活与par -2介导的ECs激活联系起来的证据。已确定的通路可能为开发治疗侵袭性脑肿瘤的其他策略提供一个有趣的靶点。
Highly malignant tumors, such as glioblastomas, are characterized by hypoxia, endothelial cell (EC) hyperplasia, and hypercoagulation. However, how these phenomena of the tumor microenvironment may be linked at the molecular level during tumor development remains ill-defined. Here, we provide evidence that hypoxia up-regulates protease-activated receptor 2 (PAR-2), i.e., a G-protein-coupled receptor of coagulation-dependent signaling, in ECs. Hypoxic induction of PAR-2 was found to elicit an angiogenic EC phenotype and to specifically up-regulate heparin-binding EGF-like growth factor (HB-EGF). Inhibition of HB-EGF by antibody neutralization or heparin treatment efficiently counteracted PAR-2-mediated activation of hypoxic ECs. We show that PAR-2-dependent HB-EGF induction was associated with increased phosphorylation of ERK1/2, and inhibition of ERK1/2 phosphorylation attenuated PAR-2-dependent HB-EGF induction as well as EC activation. Tissue factor (TF), i.e., the major initiator of coagulation-dependent PAR signaling, was substantially induced by hypoxia in several types of cancer cells, including glioblastoma; however, TF was undetectable in ECs even at prolonged hypoxia, which precludes cellautonomous PAR-2 activation through TF. Interestingly, hypoxic cancer cells were shown to release substantial amounts of TF that was mainly associated with secreted microvesicles with exosome-like characteristics. Vesicles derived from glioblastoma cells were found to trigger TF/VIIa-dependent activation of hypoxic ECs in a paracrine manner. We provide evidence of a hypoxia-induced signaling axis that links coagulation activation in cancer cells to PAR-2-mediated activation of ECs. The identified pathway may constitute an interesting target for the development of additional strategies to treat aggressive brain tumors.