Zhang Chao, Chen Wenliang, Zhang Xin, Huang Bin, Chen Aanjing, He Ying, Wang Jian, Li Xingang
Department of Neurosurgery, Qilu Hospital, Shandong University, 107 Wenhuaxi Road, Jinan, China.
Brain Science Research Institute, Shandong University, 44 Wenhuaxi Road, Jinan, China.
Sci Rep. 2016 Mar 15;6:23056. doi: 10.1038/srep23056.
Gliomas are among the most lethal primary brain tumors found in humans. In high-grade gliomas, vasculogenic mimicry is often detected and has been correlated with prognosis, thus suggesting its potential as a therapeutic target. Vasculogenic mimicry mainly forms vascular-like channels independent of endothelial cells; however, little is known about the relationship between astrocytes and vasculogenic mimicry. In our study, we demonstrated that the presence of astrocytes promoted vasculogenic mimicry. With suspension microarray technology and in vitro tube formation assays, we identified that astrocytes relied on TGF-β1 to enhance vasculogenic mimicry. We also found that vasculogenic mimicry was inhibited by galunisertib, a promising TGF-β1 inhibitor currently being studied in an ongoing trial in glioma patients. The inhibition was partially attributed to a decrease in autophagy after galunisertib treatment. Moreover, we observed a decrease in VE-cadherin and smooth muscle actin-α expression, as well as down-regulation of Akt and Flk phosphorylation in galunisertib-treated glioma cells. By comparing tumor weight and volume in a xenograft model, we acquired promising results to support our theory. This study expands our understanding of the role of astrocytes in gliomas and demonstrates that galunisertib inhibits glioma vasculogenic mimicry induced by astrocytes.
神经胶质瘤是人类发现的最致命的原发性脑肿瘤之一。在高级别神经胶质瘤中，常检测到血管生成拟态，且其与预后相关，这表明它有可能成为治疗靶点。血管生成拟态主要形成独立于内皮细胞的血管样通道；然而，关于星形胶质细胞与血管生成拟态之间的关系却知之甚少。在我们的研究中，我们证明星形胶质细胞的存在促进了血管生成拟态。通过悬浮微阵列技术和体外管腔形成试验，我们确定星形胶质细胞依赖转化生长因子-β1（TGF-β1）来增强血管生成拟态。我们还发现，目前正在胶质瘤患者中进行的一项试验中研究的一种有前景的TGF-β1抑制剂加鲁尼西替可以抑制血管生成拟态。这种抑制作用部分归因于加鲁尼西替治疗后自噬的减少。此外，我们观察到加鲁尼西替处理的胶质瘤细胞中血管内皮钙黏蛋白（VE-cadherin）和平滑肌肌动蛋白-α（smooth muscle actin-α）表达降低，以及Akt和Flk磷酸化下调。通过比较异种移植模型中的肿瘤重量和体积，我们获得了支持我们理论的有前景的结果。这项研究扩展了我们对星形胶质细胞在神经胶质瘤中作用的理解，并证明加鲁尼西替抑制星形胶质细胞诱导的胶质瘤血管生成拟态。
