组织因子介导的GBM肾小球样血管形成机制与MRI特征研究

Glioblastoma multiforme (GBM) is an extraordinarily hypervascular malignant brain tumor. A key feature of GBM is the extensive network of abnormal vasculature characterized by glomeruloid vascular proliferation (GVP), which is an independent predictor of GBM aggressiveness and patients’ outcome, and plays an important role in resistance to anti-angiogenic therapy. Yet the mechanism of GVP formation and imaging biomarkers remain poorly defined. Our previous study revealed that tissue factor (TF)can activate multiple mechanisms to form bllod vessels during tumor progression. Moreover, TF expression correlated well with the the density and distribution of GVP, and made effects on orgin of endothelial cells.Therefore, we hypothesize that TF could paly an important role in GVP formation, and the driver alterations of heterogenous TF expression may have a close relationship with the mechanism of GVP formation. Based on our previous study, this project aims to explore the molecular biological properties of heterogenous TF expression and the molecular mechanism of GVP formation, to investigate the characteristics of MR imagings, and to obtain imaging biomarkers by making correlation analysis between gene characteristics and MR imagings. By this way, it may provide theoretical basis for individualized diagnosis for glioma heterogeneity and monitoring efficacy of the targeted therapy.

胶质母细胞瘤（glioblastoma multiforme,GBM）是血管极为丰富的恶性脑肿瘤，肾小球样血管是诊断GBM的重要组织学特征，对肿瘤恶性程度、预后和抗血管生成治疗耐受有显著影响，但其分子特征及相应的影像学标志并不清楚。我们的前期研究发现，GBM内组织因子异质性表达与多种血管生成机制有关，更为重要的是与肾小球样血管内皮细胞来源、血管数量及分布密切相关，且通过下调组织因子表达可显著抑制肾小球样血管形成。因此，我们认为组织因子是肾小球样血管形成的重要驱动因子，其异质性表达的始动因素可能与肾小球样血管形成机制关系密切。本项目拟在前期研究基础上，对组织因子异质性表达的有关机制进行研究，探讨肾小球样血管形成机制及分子特征，并与肾小球样血管数量、分布以及MRI灌注表现进行相关性分析，确立肾小球样血管的影像特征以及相应生物标记，最终为胶质瘤的个体化诊断和抗血管靶向治疗效果的监测提供理论依据。

胶质母细胞瘤（Glioblastoma, GBM）是脑内最常见的极富血管恶性肿瘤，肾小球样血管是诊断GBM的重要组织学特征，然而其分子特征、调控机制和相应的影像学标志并不清楚。在本项目资助下，我们采用GBM患者临床标本、原代肿瘤模型及胶质瘤细胞系动物模型，发现：（1）TF通过独立于VEGF的PAR2/HB-EGF信号通路调节内皮细胞的增殖、迁移、成血管能力及通过调控肿瘤细胞的侵袭能力来调节肾小球样血管的形成；（2）获得调控TF表达的关键基因，其可能成为TF在肿瘤内异质性表达的始动因素；（3）采用具有TF靶向能力的磁共振分子影像纳米探针，实现活体监测胶质瘤内TF异质性表达；（4）采用DWI-MRI、DCE-MRI、DSC-MRI、VSI-MRI等多种功能磁共振序列，获得能够无创进行肿瘤分级、鉴别不同分子亚型、评价胶质瘤新生血管方式、反映胶质瘤患者TF表达及调控TF表达的关键基因的影像学标志物。总之，我们的研究明确了TF在GBM肾小球样血管形成中的作用、提供了新的胶质瘤诊疗靶标，TF介导的GBM肾小球样血管形成的分子机制和影像特征，为GBM有效抗血管生成治疗靶点筛选、病程演变监测、疗效评估提供实验依据，这对于进一步探索胶质瘤患者的个体化精准诊疗策略具有重要的科学意义和应用价值。.项目的各项研究工作按照申请书的计划进行，在各个阶段都取得了较好的进展和成果，培养了多名在相关领域从事科研工作的研究生，达到了预期目标。目前，项目组成员已发表发表相关论文22篇，其中国外SCI论文14篇，国内重要期刊论文8篇，并有其它多项研究成果正在陆续整理发表中。