细胞外蛋白Tenascin-c促进胶质瘤血管拟态形成及其机制研究

胶质瘤是一种高度血管化的实体肿瘤，然而临床上众多针对VEGF或者受体酪氨酸激酶的胶质瘤抗血管治疗疗效并不如意，提示针对经典肿瘤血管生成通路的阻断治疗存在不足之处。血管生成拟态的提出对以内皮依赖性血管是肿瘤微循环唯一方式的传统观念提出了挑战。前期研究中我们发现在胶质瘤中表达明显上调细胞外蛋白Tenascin-c（TNC）与患者不良预后密切相关，我们进一步通过体内外实验证实无论内源性还是外源性的TNC均具有促进胶质瘤血管拟态形成的功能，同时还初步证实AKT，MMP2，MMP9信号通路在其中可能发挥关键作用。本项目拟通过剖析TNC的结构，深入研究TNC与肿瘤细胞结合的关键受体，利用体内外血管拟态模型验证激活EGFR促进血管拟态形成的作用，并探讨靶向TNC抗血管治疗的作用，为利用TNC特异性抗体抑制胶质瘤血管形成的临床应用提供理论基础和实验依据。

Glioma is characterized as high vascularization tumor. However, the clinical benefit of anti-vascular therapy targeting VEGF or receptor tyrosine kinases is not satisfactory, suggesting that classical tumor angiogenesis pass way exist shortcomings. Vasculogenic mimicry challenges the traditional idea that endothelium-dependent blood vessels are the only way of tumor microcirculation. In previous studies, we found that gliomas with high Tenascin-c (TNC) expression are closely associated with poor prognosis of the patients. We further confirmed both endogenous and exogenous TNC promote glioma vasculogenic mimicry formation in vivo and in vitro. We also preliminary evidence that that AKT, MMP2, MMP9 signaling pathway may play a key role in promoting vasculogenic mimicry. In this project, we will analyze TNC protein structure and explore the key receptor which TNC combined with in glioma cell. We will further validated that activation of EGFR promote vascular mimicry formation in vivo and in vitro. We further explore the anti-angiogenesis therapy by targeting TNC, which could be potencially applied in clinic for glioma treatment.