脑胶质瘤抗血管生成治疗过程中肿瘤血管及微环境正常化的机制研究及磁共振定量评价

Tumor antiangiogenic therapy has become an important new method for the targeting treatment of tumor. The previous studies have demonstrated that tumor vascularization and microenvironment normalization were observed over a period of time after tumor targeting therapy. During this effective time window, there is a synergistic effect between antiangiogenic targeting therapy，radiotherapy and chemotherapy. This research hypothesis: glioma vasculature and microenvironment normalization also exist in the process of antiangiogenic treatment, and we can use MRI imaging quantitative parameters to evaluate the normalization process of antiangiogenic drug bevacizumab in treating glioma. This project will explore the mechanism of vasculature and microenvironment normalization in the process of glioma antiangiogenic therapy. Then the associations between multimodal MRI quantitative parameters and pathological test results of brain tumor angiogenesis and the microenvironment will be the analyzed to determine best MRI quantitative parameters in evaluating the glioma angiogenesis and the microenvironment changes. Furthermore, the effective time window for normalization of tumor vasculature and microenvironment of glioma after antiangiogenic therapy will be clarified by multimodal MRI and pathological tests. The last step is to verify the synergistic effect of targeted antiangiogenic drugs，radiotherapy and chemotherapy for treatment of glioma in effective time window. This research is of great value in evaluating the effect of glioma antiangiogenic targeting treatment by MR imaging and guiding for the appropriate time point of comprehensive treatment with antiangiogenic therapy, radiotherapy and chemotherapy.

肿瘤抗血管靶向治疗已成为治疗肿瘤的重要新方法。研究表明肿瘤在抗血管靶向治疗后，有一段能使肿瘤微血管和微环境趋于正常化的时间窗，在此“有效时间窗内”抗血管靶向药物与放化疗治疗可产生协同作用。我们假设：脑胶质瘤抗血管治疗过程中也存在肿瘤血管和微环境正常化现象，并可以用MRI成像定量参数无创性评估抗血管药物贝伐单抗治疗胶质瘤后肿瘤血管和微环境正常化过程。本项目将探讨脑胶质瘤抗血管治疗过程中肿瘤血管和微环境正常化机制，使用多模态MRI检查定量参数与脑肿瘤微血管和微环境的病理检测结果进行相关性分析，确定评估肿瘤血管和微环境变化的最佳MRI定量参数，明确脑胶质瘤抗血管治疗后“肿瘤血管和微环境正常化时间窗”，并验证在“有效时间窗内”靶向抗血管药物与放化疗的协同作用效果。本项目对于脑胶质瘤靶向肿瘤效果的评估及指导临床靶向治疗联合放化疗治疗时机的选择，具有重要的应用价值。

肿瘤的生长主要依赖新生血管的生成，新生血管为肿瘤生长提供氧气和营养。抗肿瘤血管生成是目前重要的抗肿瘤治疗策略之一。有研究发现应用抗血管生成药物会使肿瘤血管系统在一段时间内趋于正常化，即“正常化时间窗”，在这一时间窗内进行放化疗可增加其疗效。但如何无创准确监测肿瘤血管正常化时间窗是一大难题。本研究通过建立大鼠原位胶质瘤模型，经贝伐单抗抗血管治疗后，在不同时间点（治疗后0天、2天、4天、6天、8天）通过磁共振成像动态监测并与病理组织学指标进行相关性分析，发现贝伐单抗治疗后大鼠C6肿瘤的生长明显减慢，随着时间的推移，肿瘤体积的差异变得越来越大；贝伐单抗治疗后第2天和第4天，治疗组f和fD*逐渐升高，显著高于对照组，并在第6天和第8天逐渐降低。对照组和治疗组的灌注参数f和fD*与MVD呈正相关。治疗组f与α-SMA/CD34呈正相关，而fD*与此关联性差。治疗组f和fD*与HIF-1α呈轻微正相关。即IVIM-MRI参数（f及fD*）能较好反应胶质瘤血管和微环境变化，贝伐单抗治疗胶质瘤的血管正常化时间窗为抗血管生成治疗后2-4天。电子显微镜检查也观察到治疗组第2-4天，肿瘤血管基底膜和紧密连接较对照组完整。我们的研究结果表表明，胶质瘤抗血管生成治疗血管正常化时间窗为治疗后第2-4天，并可以用IVIM-DWI成像无创检测。本课题组还在胶质瘤颅内压和脑脊液循环方面做了部分拓展研究。发现肿瘤大鼠的颅内压较正常大鼠颅内压增高，脑脊液循环受阻，肿瘤区域的AQP4表达量下降，这个发现为脑肿瘤的药物治疗策略提供了新的思路。