IGF binding protein-6 expression in vascular endothelial cells is induced by hypoxia and plays a negative role in tumor angiogenesis.
IGF binding protein-6 expression in vascular endothelial cells is induced by hypoxia and plays a negative role in tumor angiogenesis.
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DOI：
10.1002/ijc.26201
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发表时间：
2012-05-01
影响因子：
6.4
通讯作者：
Duan, Cunming
中科院分区：
文献类型：
--
作者：
Zhang, Chunyang;Lu, Ling;Li, Yun;Wang, Xianlei;Zhou, Jianfeng;Liu, Yunzhang;Fu, Ping;Gallicchio, Marisa A.;Bach, Leon A.;Duan, Cunming
缺氧通过诱导血管生成分子的表达刺激肿瘤血管生成。然而，这一过程的负面调节因素还没有得到很好的理解。在这里，我们报道了缺氧通过hif介导的机制诱导人和啮齿动物血管内皮细胞（VECs）中肿瘤抑制因子胰岛素样生长因子结合蛋白6 （IGFBP-6）的表达。体外培养的人血管内皮细胞中加入人IGFBP-6抑制血管生成。IGFBP-6突变体对igf的结合亲和力至少降低了1万倍，但它同样有效地抑制了血管生成，这表明IGFBP-6的这种作用与igf无关。研究IGFBP-6与VEGF（一种主要的缺氧诱导血管生成分子）之间的功能关系。虽然VEGF单独增加体外血管生成，但与IGFBP-6共孵育可消除VEGF刺激的血管生成。在flk1:GFP斑马鱼胚胎中测试了IGFBP-6在血管生成中的体内作用，该胚胎在发育的血管内皮中表现出绿色荧光蛋白，可以看到正在发育的血管。注射人IGFBP-6 mRNA可使胚胎节段间血管数量减少约40%。这种抗血管生成活性在斑马鱼中是保守的，因为斑马鱼IGFBP-6b的表达具有类似的作用。为了确定IGFBP-6在肿瘤模型中的抗血管生成作用，我们将稳定转染IGFBP-6的人Rh30横纹肌肉瘤细胞接种于胸腺BALB/c裸鼠。转染igfbp -6的异种移植物的血管密度比载体对照的异种移植物低52%。这些结果表明，缺氧可上调VECs中IGFBP-6的表达，IGFBP-6在体外和体内均抑制血管生成。
Hypoxia stimulates tumor angiogenesis by inducing the expression of angiogenic molecules. The negative regulators of this process, however, are not well understood. Here we report that hypoxia induced the expression of insulin-like growth factor binding protein-6 (IGFBP-6), a tumor repressor, in human and rodent vascular endothelial cells (VECs) via a HIF-mediated mechanism. Addition of human IGFBP-6 to cultured human VECs inhibited angiogenesis in vitro. An IGFBP-6 mutant with at least 10,000-fold lower binding affinity for IGFs was an equally potent inhibitor of angiogenesis, suggesting that this action of IGFBP-6 is IGF-independent. The functional relationship between IGFBP-6 and VEGF, a major hypoxia-inducible angiogenic molecule, was examined. While VEGF alone increased angiogenesis in vitro, co-incubation with IGFBP-6 abolished VEGF-stimulated angiogenesis. The in vivo role of IGFBP-6 in angiogenesis was tested in flk1:GFP zebrafish embryos, which exhibit green fluorescence protein in developing vascular endothelium, permitting visualization of developing blood vessels. Injection of human IGFBP-6 mRNA reduced the number of embryonic inter-segmental blood vessels by ∼40%. This anti-angiogenic activity is conserved in zebrafish because expression of zebrafish IGFBP-6b had similar effects. To determine the anti-angiogenic effect of IGFBP-6 in a tumor model, human Rh30 rhabdomyosarcoma cells stably transfected with IGFBP-6 were inoculated into athymic BALB/c nude mice. Vessel density was 52% lower in IGFBP-6-transfected xenografts than in vector control xenografts. These results suggest that the expression of IGFBP-6 in VECs is up-regulated by hypoxia and IGFBP-6 inhibits angiogenesis in vitro and in vivo.
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影响因子：
15.9
作者：
Kondo, T;Vicent, D;Kahn, CR
通讯作者：
Kahn, CR
影响因子：
4.8
作者：
Li, Y;Xiang, JH;Duan, CM
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Duan, CM
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64.8
作者：
Maxwell, PH;Wiesener, MS;Ratcliffe, PJ
通讯作者：
Ratcliffe, PJ
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5.3
作者：
Kajimura, S;Aida, K;Duan, CM
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Duan, CM
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4.8
作者：
Iosef, Cristiana;Vilk, Gregory;Han, Victor K.
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Han, Victor K.