慢性应激对胶质瘤恶性生物学行为的调控作用及机制研究

High malignancy and high mortality of glioma make it urgent to elucidate the underlying mechanisms of glioma carcinogenesis and explore novel targets for glioma therapy. Epidemiologic and clinical studies have shown that chronic stress may promote the progression of various solid tumors, and is correlated with patient’s poor prognosis. Yet, findings reporting the involvement of chronic stress in glioma are rare. In previous study, we found out that chronic stress could enhance the malignant behavior of glioma cells and glioma stem cells (GSCs). In this project, chronic stress mouse model with intracranial cell transplantation and tumor cell specific techniques will be used to further evaluate the role of chronic stress and stress-hormones in glioma. Furthermore, the target and the downstream signaling of chronic stress in glioma cell will be investigated using high-throughput screening and classic molecular biological techniques. In addition, the correlation between the activated pathways and the targets of chronic stress in glioma with the clinicopathological characteristics and the prognosis of patients will be studied in order to identify a novel biomarker for the prognosis of glioma.

胶质瘤恶性程度高、预后差，深入研究胶质瘤发生发展的调控机制，探寻治疗新靶点已迫在眉睫。已有大量的流行病学调查和临床研究表明，慢性应激可以促进肿瘤的进展，且与病人的预后不良密切相关，但其在胶质瘤进展中的调控作用尚无报道。我们前期研究发现慢性应激极有可能在胶质瘤恶性生物学行为中发挥了重要的调控作用。在本项目中，我们将利用经典的慢性应激动物模型和细胞学实验，从体内和体外检测慢性应激及应激激素对胶质瘤增殖、侵袭和干性的调控作用；再利用高通量的测序技术和经典的信号转导研究技术，寻找应激激素的作用靶点和调控的信号通路，阐明慢性应激调控胶质瘤恶性生物学行为的分子机制；利用临床胶质瘤样本，分析调控通路的节点分子及作用靶点的表达水平与临床病理及患者预后的相关性，探讨其作为胶质瘤预后判定标志物的可行性。希望通过本课题的实施，为胶质瘤的治疗提供新思路和新靶标。

在本项目的研究中，我们发现慢性应激及应激关键激素能够促进胶质瘤在动物体内的生长，同时利用细胞学实验发现其能够促进胶质瘤细胞的增殖、迁移以及干细胞扩增；进一步的机制研究发现，应激激素分别结合糖皮质激素受体和b-型肾上腺素能受体，并活化PI3K/Akt信号通路、上调Twist1表达、促进胶质瘤细胞发生EMT样变化，从而发挥其调控作用。此外，利用多个胶质瘤数据库的样本信息对应激的靶基因Twist1进行了表达分析及预后分析，结果显示Twist1的表达水平随胶质瘤恶性程度增加而升高，Twist1高表达与肿瘤复发、预后不良密切相关，提示Twist1在胶质瘤的预后判定中具有潜在应用价值。通过本项目的开展我们发现慢性应激促进胶质瘤的恶性生物学行为，并探究了其调控机制，研究结果有望为保护胶质瘤患者免受应激对肿瘤进展的不利影响提供潜在的治疗靶点和新的策略。