Glioblastoma-secreted factors induce IGFBP7 and angiogenesis by modulating Smad-2-dependent TGF-β signaling
Glioblastoma-secreted factors induce IGFBP7 and angiogenesis by modulating Smad-2-dependent TGF-β signaling
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DOI：
10.1038/onc.2008.287
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发表时间：
2008-11-20
期刊：
影响因子：
8
通讯作者：
Stanimirovic, D. B.
中科院分区：
文献类型：
--
作者：
Pen, A.;Moreno, M. J.;Stanimirovic, D. B.
胰岛素样生长因子结合蛋白7 （IGFBP7）是胶质母细胞瘤（GBM）血管的选择性生物标志物，在肿瘤内皮细胞和血管基底膜中强烈表达。IGFBP7基因调控及其在肿瘤血管生成中的潜在作用尚不清楚。在暴露于肿瘤样条件下的人脑内皮细胞（HBECs）中，研究了IGFBP7诱导及其血管生成能力的机制。用GBM细胞（U87MG）条件培养基（-CM）处理的HBEC与对照细胞相比，IGFBP7 mRNA和蛋白上调了4倍。IGFBP7基因在HBEC中的调控与甲基化无关。酶联免疫吸附试验分析U87MG-CM含有类似于5 pM转化生长因子(TGF)- β 1的浓度，足以刺激HBEC中的IGFBP7达到与U87MG-CM相似的水平。泛tgf - β中和抗体（1D11）和tgf - β 1受体（激活素受体样激酶5，ALK5）拮抗剂SB431542均可阻断u87mg - cm诱导的HBEC中IGFBP7的表达，表明tgf - β 1是内皮细胞中能够诱导IGFBP7的重要肿瘤分泌效应物。暴露于U87MG-CM或IGFBP7蛋白的HBEC在Matrigel中表现出增加的毛细管样管（CLT）形成。在HBEC中，tgf - β 1-和u87mg - cm诱导的Smad-2磷酸化和u87mg - cm诱导的CLT形成均被ALK5拮抗剂SB431542抑制。这些数据表明，促血管生成的IGFBP7可能是由GBM分泌的tgf - β s诱导的，很可能是通过tgf - β 1/ALK5/Smad-2通路。中华肿瘤杂志（2008）27 (2):634 - 644；doi: 10.1038 / onc.2008.287;于2008年8月18日在网上发表
Insulin-like growth factor-binding protein 7 (IGFBP7) is a selective biomarker of glioblastoma (GBM) vessels, stronglyexpressed in tumor endothelial cells and vascular basement membrane. IGFBP7 gene regulation and its potential role in tumor angiogenesis remain unclear. Mechanisms of IGFBP7 induction and its angiogenic capacity were examined in human brain endothelial cells (HBECs) exposed to tumor-like conditions. HBEC treated with GBM cell (U87MG)-conditioned media (-CM) exhibited fourfold upregulation of IGFBP7 mRNA and protein compared to control cells. IGFBP7 gene regulation in HBEC was methylation independent. U87MG-CM analysed by enzyme-linked immunosorbent assay contained similar to 5 pM transforming growth factor (TGF)-beta 1, a concentration sufficient to stimulate IGFBP7 in HBEC to similar levels as U87MG-CM. Both pan-TGF-beta-neutralizing antibody(1D11) and the TGF-beta 1 receptor (activin receptor-like kinase 5, ALK5) antagonist, SB431542, blocked U87MG-CM-induced IGFBP7 expression in HBEC, indicating that TGF-beta 1 is an important tumor-secreted effector capable of IGFBP7 induction in endothelial cells. HBEC exposed to either U87MG-CM or IGFBP7 protein exhibited increased capillary-like tube (CLT) formation in Matrigel. Both TGF-beta 1- and U87MG-CM-induced Smad-2 phosphorylation and U87MG-CM-induced CLT formation in HBEC were inhibited by the ALK5 antagonist, SB431542. These data suggest that proangiogenic IGFBP7 maybe induced in brain endothelial cells by TGF-beta s secreted by GBM, most likely through TGF-beta 1/ALK5/Smad-2 pathway. Oncogene (2008) 27, 6834-6844; doi: 10.1038/onc.2008.287; published online 18 August 2008