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.

中文翻译：

---

IGFBP2通过调节神经胶质瘤中CD144和MMP2的表达来促进血管生成模拟物的形成。

血管生成模拟（VM）是指由侵袭性肿瘤细胞而非内皮细胞（EC）形成的具有流体传导通道，这些通道具有与血管化相关的基因表达升高。VM被认为是胶质母细胞瘤对抗VEGF治疗产生耐药性的原因之一。但是，尚不清楚VM形成的分子基础。在这里，我们报告胰岛素样生长因子结合蛋白2（IGFBP2）作为增强脑胶质瘤VM形成的有效因子。有证据表明，IGFBP2表达升高与脑胶质瘤患者的VM形成呈正相关。通过激活CD144和MMP2（基质金属蛋白酶2），IGFBP2的强制表达增加了神经胶质瘤细胞网络的形成。在原位小鼠模型中，具有稳定的IGFBP2抑制作用的U251细胞导致VM形成减少和肿瘤进展。从机制上讲，IGFBP2与整联蛋白α5和β1亚基相互作用，并以FAK / ERK途径依赖性方式增强CD144的表达。萤光素酶报告基因和ChIP分析表明，IGFBP2激活了转录因子SP1，该转录因子可以与CD144启动子结合。因此，IGFBP2通过增强CD144和MMP2的表达作为神经胶质瘤细胞中VM形成的刺激物。