神经胶质瘤相关小胶质细胞通过释放细胞因子对肿瘤的生长、侵袭、免疫逃避、化疗耐受起到促进作用。乳脂肪球表皮生长因子8 蛋白（MFG-E8），是一种分泌型糖蛋白,与组织稳态和肿瘤免疫应答密切相关。我们发现MFG-E8高表达于卡氮介耐受胶质瘤细胞中，并且沉默其表达可增高对卡氮芥的敏感性。进一步发现，MFG-E8诱导小胶质细胞IL-10和TGF-b表达而抑制LPS诱导M1炎性因子表达。这些结果提示MFG-E8可能在神经肿瘤微环境调控中起重要作用。以此为基础，本课题将研究: 1) MFG-E8对小胶质细胞M1/M2活化作用及其信号转导机制；2) MFG-E8对神经胶质瘤卡氮芥治疗敏感性作用及其信号机制；3) 肿瘤微环境因子对神经胶质瘤和小胶质细胞MFG-E8表达机制。肿瘤微环境中的MFG-E8在神经胶质瘤化疗耐受产生中的作用和分子机制，同时也可能为神经胶质瘤的治疗提供新的靶点。

Tumor associated microglia promotes tumor growth, invasion and immunosuppression and chemoresistance by release of cytokines and extracelluar matrix proteases instead of initiating the anti-tumor response. Milk fat globule EFG-8(MFG-E8), a secreted glycoprotein is closely related to tissue homeostasis and immune response in tumor. In previous study, we found that MFG-E8 was upregulated in BCNU-resistant C6 glioma cells and that knockdown of MFGE-E8 by shRNA significantly increased sesitivity of GL261 glioma cells to BCNU. We also found that the recombinant MFG-E8 significantly induced TGF-b and IL-10 production in BV-2 microglia cells. In addition, recombinant MFG-E8 also reduced the expression of IL-1b and TNF-a in LPS stimulated BV-2 microglia cells. These results indicate that MFG-E8 may play a key role in glioma chemoresistance and glioma microenvironment. Based on our previous study, this project is to investigate the following subjects: 1. the effects and molecular mechanisms of MFG-E8 on microglial polarization; 2. the effects and molecular mechanisms of MFG-E8 in glioma chemoresistance；3. the effects and molecular mechanisms of microinvironmental factor on MFG-E8 expression in glioma or microglia cells. This study may provide a new explanation of mechanisms of glioma microenvironment regulation and glioma development,and futher provide a new potential target for immunotherapy and drug development for glioma.

乳脂肪球表皮生长因子8 蛋白（MFG-E8），是一种分泌型糖蛋白,与组织稳态和肿瘤免疫应答密切相关。我们前期研究发现MFG-E8诱导小胶质细胞IL-10和TGF-b表达而抑制LPS诱导的促炎因子表达。这些结果提示MFG-E8 在小胶质细胞介导的神经胶质瘤微环境中起免疫抑制作用。本研究发现：1）重组MFG-E8、内源性过表达MFG-E8通过intergrin beta3/STAT3 信号途径促进小胶质细胞M2型转化，抑制LPS诱导M1型转化; 2）干扰MFG-E8表达通过抑制STAT3/ciclinD1 和intergrin beta3/AKT/ERK 信号途径抑制胶质瘤细胞增殖以及增加化疗药物敏感性; 3）GL261细胞脑内原位接种模型中，GL261沉默MFG-E8明显降低小胶质细胞表达M2相关标记物并且减慢肿瘤生长以及延长小鼠生存率; 4）胶质瘤细胞上清中TGF-b1, IL-10 和GM-CSF诱导小胶质细胞MFG-E8 表达。这些结果阐明了MFG-E8 表达神经胶质瘤及其微环境调控机制，为神经胶质瘤的药物发现提供新的思路。