基于高场MRI/S的谷氨酰胺/血管生成变化在脑胶质瘤浸润中的作用研究

Glioma is the most common malignant tumor in the brain. Complete resection is very difficult for glioma and it is easy to recur. The clinical outcome is very poor. Glioma can rapidly invasively grow in the early stage, and the boundary between glioma and normal tissue is hard to be distinguished. However, the mechanism of brain glioma infiltration is not clear. Previous studies show that glutamine and angiogenesis may play an important role in glioma invasion, but in-depth studies are still rare, and there are no imaging evidences. In this project, based on the rat C6 glioma model and glioma patients, peritumoral infiltrations were detected and investigated using MR methods such as vessel imaging, spectral imaging, and OE-MRI, and so on, at 9.4 T high field (for animals) and 3.0 T (for patients), combined with microdialysis, liquid NMR, and pathology. Specific aims of the projects are: 1) to determine the MRI/S characteristics of the glioma infiltration, 2) to investigate the effect of hypoxia and changes of glutamate/glutamine on the angiogenesis in peritumoral region, 3) to determine the correlation between the MRI/S characteristics and the changes in pathology of hypoxia, glutamate/glutamine and angiogenesis. The research results will provide the glioma invasion with direct imaging evidence, and lay the foundation for future work related to therapeutic strategies, such as clinical biological intensity modulated radiotherapy, anti-angiogenic chemotherapy and targeted drug therapy, etc. as well as the evaluation of therapeutic efficacy.

脑胶质瘤是颅内最常见的恶性肿瘤，手术全切除难度很大且易复发，临床治疗效果很差。脑胶质瘤早期即可形成浸润性快速生长，与正常组织界限不清。然而，脑胶质瘤浸润的机制尚不清楚。研究提示谷氨酰胺/血管生成可能对脑胶质瘤浸润起重要作用，但深入的研究还非常少，而且尚缺乏临床神经影像学证据。本项目拟以大鼠C6脑胶质瘤模型和脑胶质瘤病人为研究对象，利用9.4T高场和3T磁共振血管成像、波谱成像、氧增强磁共振成像等技术，结合微透析、液体核磁共振、病理学方法对脑胶质瘤浸润区的病理机制进行研究。研究内容包括脑胶质瘤浸润的影像/波谱学特征，乏氧和谷氨酸/谷氨酰胺对血管生成的作用，以及脑胶质瘤浸润的影像学特征与乏氧、谷氨酸/谷氨酰胺和血管生成等病理改变之间的关联。研究结果将为脑胶质瘤浸润的病理研究提供直观的影像学证据，为脑胶质瘤临床生物适形调强放疗、抗血管生成化疗和靶向药物治疗方法及判断治疗疗效奠定重要的实验基础。

胶质母细胞瘤是成人最常见的侵袭性原发性肿瘤，对传统治疗高度抵抗，生存时间短，死亡率高。胶质母细胞瘤的关键特征之一是丰富的血管系统，为肿瘤的增殖和发展提供了必要的环境条件。抑制肿瘤血管生成将在很大程度上阻断氧气和营养的供应。研究表明，谷氨酰胺合成酶（GS）可以通过改善内皮细胞迁移来诱导眼和炎症性疾病中血管生成。蛋氨酸亚砜酰亚胺（MSO）是谷氨酰胺合成酶的不可逆竞争性抑制剂，可有效抑制谷氨酰胺合成酶的活性。MSO还可以通过调节肿瘤细胞的运动来调节内皮毛细血管的形成和转移，从而抑制血管生成。然而，谷氨酰胺合酶对胶质瘤血管生成和肿瘤治疗的影响尚未有报道。.基于大鼠C6脑胶质瘤模型，本项目应用高场磁共振血管大小成像（magnetic resonance vessel size imaging）技术研究了大鼠脑胶质瘤血管生成变化。高场磁共振成像结果显示血管形态变化主要发生在肿瘤中心。GS抑制剂（MSO）治疗后4天，肿瘤中心的定量微血管密度（Density）与正常部位的水平相比显著下降。与对照组相比，MSO治疗组肿瘤生长也明显受到抑制。该结果经由免疫荧光实验证实，与对应的对侧纹状体染色结果相比，MSO组肿瘤侧中心部位CD31的表达显著降低，表明MSO影响了新生血管的生长，微血管密度降低；同时，对照组中肿瘤侧部位CD31的表达相对较高。结果表明，CD31表达的降低提示原位C6胶质母细胞瘤对MSO的治疗反应较好。与对照组相比，MSO组肿瘤侧中心部位的CD31蛋白显著下调。以上结果表明磁共振血管大小成像技术可为脑胶质瘤的血管生成提供有价值的信息，并有可能成为GS在胶质瘤新生血管形成中的作用研究的新工具。