肿瘤干细胞转分化在间质型胶质母细胞瘤抵抗贝伐单抗治疗中的作用及机制

Vascular endothelial growth factor (VEGF) pathway critically contributes to tumor angiogenesis and supports the self-renewal of cancer stem cells. Bevacizumab, a humanized anti-VEGF antibody, exerts differential effects on heterogeneous glioblastomas (GBMs) with different subtypes. Previous studies indicate that only the proneural GBMs, but not the mesenchymal GBMs, may benefit from Bevacizumab treatment, while the underlying mechanism remains largely unknown. Our previous results indicate that increased percentage of pericytes in GBMs may mediate therapeutic resistance and informs poor prognosis of GBM patients. Since pericytes in GBMs can be derived from cancer stem cells and our preliminary results indicate that Bevacizumab treatment markedly increases the proportion of GSC-derived pericytes in mesenchymal GBMs, we propose that Bevacizumab treatment could induce cancer stem cells to transdifferentiate into pericytes thus promote mesenchymal GBMs to escape from the anti-tumor effect. In this project, we will employ in vitro and in vivo cell tracing system with lineage-specific fluorescent reporters to determine the effect of Bevacizumab treatment on cancer stem cells-pericyte transdifferentiation in different subtypes of GBMs, as well as the underlying mechanism and the therapeutic significance. Different subtypes of human GBM specimens that treated with or without Bevacizumab from our hospital and those from the clinical database will be employed to investigate the pathological significance. Our results may provide new insights for the precise anti-angiogenic therapeutic strategy based on GBM molecular classification.

血管内皮生长因子（VEGF）不仅在促血管生成中非常关键，也是维持肿瘤干细胞自我更新的重要分子。VEGF的人源化抗体——贝伐单抗对不同分子亚型胶质母细胞瘤（GBM）治疗效果存在差异，其中前神经元型GBM患者受益显著，而间质型GBM疗效差、易耐药、机制不清。我们前期发现，GBM血管周细胞能介导GBM耐药，且血管周细胞数量越多，患者预后越差。鉴于GBM血管周细胞可由肿瘤干细胞转分化而来，且贝伐单抗治疗可诱导间质型GBM中血管周细胞增多，我们推测“贝伐单抗治疗可诱导肿瘤干细胞向血管周细胞转分化，从而导致间质型GBM耐药”。本课题拟以前神经元型GBM为对照，通过体内外示踪模型探讨贝伐单抗对不同分子亚型GBM肿瘤干细胞向血管周细胞转分化的诱导作用、分子机制及治疗意义，并通过人GBM组织和数据库验证。本研究将为基于分子亚型的GBM精准抗血管生成治疗策略提供依据。

贝伐单抗是临床治疗胶质母细胞瘤的重要药物之一。然而，其对不同分子亚型胶质母细胞瘤治疗效果存在差异，其中间质型胶质母细胞瘤疗效差、易耐药、机制不清。在本项目资助下，我们发现贝伐单抗处理通过诱导CEBPD表达促进胶质瘤干细胞向血管周细胞转分化，进而促进间质型胶质母细胞瘤侵袭, 揭示了贝伐单抗治疗在间质型胶质母细胞瘤中远期疗效欠佳的原因。发现贝伐单抗治疗可改变间质型胶质母细胞瘤移植瘤局部免疫微环境，以侵袭前沿小胶质细胞增多和炎症通路TNF-NFκB激活为主；小胶质细胞分泌TNF-α，激活NFκB通路，促进胶质瘤干细胞CEBPD表达上调进而促进其侵袭及向血管周细胞转分化，阐明了胶质瘤免疫微环境和胶质瘤干细胞的相互作用在贝伐单抗治疗抵抗中的机制及治疗学意义。此外，我们描绘了胶质母细胞瘤侵袭前沿血管免疫微环境特征，建立定量反应胶质母细胞瘤侵袭的新方法，为从病理学层面快速便捷评估胶质母细胞瘤侵袭提供了重要支撑。发现胶质瘤干细胞转分化而来的血管周细胞通过高分泌CCL5激活其受体CCR5促进肿瘤细胞抵抗替莫唑胺治疗，建立了基于血管周细胞的胶质瘤分型，明确其治疗学意义。本项目研究成果为基于分子亚型的胶质母细胞瘤精准抗血管生成治疗策略提供依据。在Cell Res杂志发表论著1篇（IF=25.617），获授权发明专利2件，参与会议交流3次。此外，尚有投稿阶段论文2篇。项目负责人获“英雄杯实验医学杰出青年奖”，培养“重庆市博士后创新人才支持计划”获得者1名，博士研究生3名，硕士研究生3名。