Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangzhou, China.
Oncogene. 2019 Mar;38(11):1815-1831. doi: 10.1038/s41388-018-0525-4. Epub 2018 Oct 27.
Vasculogenic mimicry (VM) refers to the fluid-conducting channels formed by aggressive tumor cells rather than endothelial cells (EC) with elevated expression of genes associated with vascularization. VM has been considered as one of the reasons that glioblastoma becomes resistant to anti-VEGF therapy. However, the molecular basis underlying VM formation remains unclear. Here we report that the insulin-like growth factor-binding protein 2 (IGFBP2) acts as a potent factor to enhance VM formation in glioma. Evidence showed that elevated IGFBP2 expression was positively related with VM formation in patients with glioma. Enforced expression of IGFBP2 increased network formation of glioma cells in vitro by activating CD144 and MMP2 (Matrix Metalloproteinase 2). U251 cells with stable knockdown of IGFBP2 led to decreased VM formation and tumor progression in orthotopic mouse model. Mechanistically, IGFBP2 interacts with integrin α5 and β1 subunits and augments CD144 expression in a FAK/ERK pathway-dependent manner. Luciferase reporter and ChIP assay suggested that IGFBP2 activated the transcription factor SP1, which could bind to CD144 promoter. Thus, IGFBP2 acts as a stimulator of VM formation in glioma cells via enhancing CD144 and MMP2 expression.
血管生成拟态（VM）是指由具有高表达与血管生成相关基因的侵袭性肿瘤细胞形成的流体传导通道，而非内皮细胞（EC）。VM 被认为是导致胶质母细胞瘤对抗血管生成治疗产生耐药性的原因之一。然而，VM 形成的分子基础仍不清楚。本文报道胰岛素样生长因子结合蛋白 2（IGFBP2）作为一种增强胶质瘤中 VM 形成的有效因子。有证据表明，IGFBP2 表达水平升高与胶质瘤患者 VM 形成呈正相关。IGFBP2 的过表达可通过激活 CD144 和 MMP2（基质金属蛋白酶 2）增加胶质瘤细胞体外网络形成。在稳定敲低 IGFBP2 的 U251 细胞中，VM 形成和肿瘤进展减少。在机制上，IGFBP2 与整合素 α5 和β1 亚基相互作用，并通过 FAK/ERK 通路依赖性方式增强 CD144 的表达。荧光素酶报告基因和 ChIP 实验表明，IGFBP2 激活转录因子 SP1，后者可以与 CD144 启动子结合。因此，IGFBP2 通过增强 CD144 和 MMP2 的表达，在胶质瘤细胞中充当 VM 形成的刺激因子。
