Autocrine VEGF-VEGFR2-Neuropilin-1 signaling promotes glioma stem-like cell viability and tumor growth.
Autocrine VEGF-VEGFR2-Neuropilin-1 signaling promotes glioma stem-like cell viability and tumor growth.
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DOI：
10.1084/jem.20111424
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发表时间：
2012-03-12
期刊：
影响因子：
--
通讯作者：
Bartek J
中科院分区：
文献类型：
--
作者：
Hamerlik P;Lathia JD;Rasmussen R;Wu Q;Bartkova J;Lee M;Moudry P;Bartek J Jr;Fischer W;Lukas J;Rich JN;Bartek J
胶质瘤干细胞样细胞中自分泌VEGFR 2信号传导逃避VEGF中和尽管血管内皮生长因子（VEGF）受体2（VEGFR 2）传统上被认为是内皮细胞蛋白，但有证据表明VEGFRs可由癌细胞表达。多形性胶质母细胞瘤（GBM）是一种以血管生成旺盛和VEGF异常升高为特征的致死性肿瘤。使用人源化VEGF抗体贝伐单抗的抗血管生成疗法减少GBM肿瘤生长;然而，临床益处是短暂的，并且总是伴随着肿瘤复发。在这项研究中，我们表明，VEGFR 2优先表达的CD 133+人胶质瘤干细胞样细胞（GSC），其活力，自我更新和致瘤性的细胞表面上依赖，至少部分地，通过VEGF-VEGFR 2-神经纤毛蛋白-1（NRP 1）轴的信号转导。我们发现，贝伐珠单抗介导的VEGF阻断的有限影响可能反映了通过VEGF-VEGFR 2-NRP 1进行的自分泌信号传导，其与VEGFR 2-NRP 1再循环和人GBM细胞亚群的胞质隔室内的活性VEGFR 2库相关。尽管贝伐珠单抗未能抑制VEGFR 2介导的信号传导的促存活作用，但通过直接抑制VEGFR 2酪氨酸激酶活性和/或shRNA介导的VEGFR 2或NRP 1敲低，在未受干扰或辐射诱发的应激条件下的GSC活力减弱。我们提出直接抑制VEGFR 2激酶可能阻断高度动态的VEGF-VEGFR 2-NRP 1通路，并激发GBM治疗策略，以补充目前流行的配体中和方法。
Autocrine VEGFR2 signaling in glioma stem-like cells evades VEGF neutralization. Although vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) is traditionally regarded as an endothelial cell protein, evidence suggests that VEGFRs may be expressed by cancer cells. Glioblastoma multiforme (GBM) is a lethal cancer characterized by florid vascularization and aberrantly elevated VEGF. Antiangiogenic therapy with the humanized VEGF antibody bevacizumab reduces GBM tumor growth; however, the clinical benefits are transient and invariably followed by tumor recurrence. In this study, we show that VEGFR2 is preferentially expressed on the cell surface of the CD133+ human glioma stem-like cells (GSCs), whose viability, self-renewal, and tumorigenicity rely, at least in part, on signaling through the VEGF-VEGFR2–Neuropilin-1 (NRP1) axis. We find that the limited impact of bevacizumab-mediated VEGF blockage may reflect ongoing autocrine signaling through VEGF–VEGFR2–NRP1, which is associated with VEGFR2–NRP1 recycling and a pool of active VEGFR2 within a cytosolic compartment of a subset of human GBM cells. Whereas bevacizumab failed to inhibit prosurvival effects of VEGFR2-mediated signaling, GSC viability under unperturbed or radiation-evoked stress conditions was attenuated by direct inhibition of VEGFR2 tyrosine kinase activity and/or shRNA-mediated knockdown of VEGFR2 or NRP1. We propose that direct inhibition of VEGFR2 kinase may block the highly dynamic VEGF–VEGFR2–NRP1 pathway and inspire a GBM treatment strategy to complement the currently prevalent ligand neutralization approach.
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影响因子：
11.2
作者：
Folkins C;Shaked Y;Man S;Tang T;Lee CR;Zhu Z;Hoffman RM;Kerbel RS
通讯作者：
Kerbel RS
影响因子：
64.8
作者：
Bartkova, J;Horejsi, Z;Bartek, J
通讯作者：
Bartek, J
影响因子：
3.6
作者：
Graeven, U;Fiedler, W;Hossfeld, DK
通讯作者：
Hossfeld, DK
影响因子：
3
作者：
Hlobilkova, A.;Ehrmann, J.;Kolar, Z.
通讯作者：
Kolar, Z.
影响因子：
--
作者：
Iwamoto FM;Fine HA
通讯作者：
Fine HA