FTY720 Exerts Anti-Glioma Effects by Regulating the Glioma Microenvironment Through Increased CXCR4 Internalization by Glioma-Associated Microglia
FTY720 Exerts Anti-Glioma Effects by Regulating the Glioma Microenvironment Through Increased CXCR4 Internalization by Glioma-Associated Microglia
复制标题
FTY720 通过增加胶质瘤相关小胶质细胞的 CXCR4 内化来调节胶质瘤微环境，从而发挥抗胶质瘤作用
DOI：
10.3389/fimmu.2020.00178
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发表时间：
2020-03-04
影响因子：
7.3
通讯作者：
Sun, Xiu-Lan
中科院分区：
文献类型：
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作者：
Guo, Xu-Dong;Ji, Juan;Sun, Xiu-Lan
背景：胶质母细胞瘤（GBM）是恶性和侵袭性最强的原发性脑肿瘤之一。胶质瘤的不可治愈性在很大程度上受胶质瘤微环境的影响。FTY720是一种有效的免疫抑制剂，已被报道在胶质母细胞瘤中发挥抗肿瘤作用。然而，FTY720对胶质瘤微环境的影响尚不清楚。方法：采用免疫荧光染色法检测FTY720对胶质瘤大鼠胶质瘤相关小胶质细胞和巨噬细胞（GAMs）分布和极化的影响。采用qRT-PCR和Western blotting检测共培养系统中CXCR4和MAPK通路相关信号分子在小胶质细胞上的表达。ELISA法检测各组炎症因子水平。采用创伤愈合实验和Matrigel侵袭实验检测C6胶质瘤细胞的迁移和侵袭。结果：我们发现FTY720可以通过靶向GAMs抑制胶质瘤细胞对胶质瘤细胞的影响，从而抑制胶质瘤的生长、迁移和侵袭。同时，FTY720可以通过增加CXCR4的内化，抑制mapk介导的IL-6分泌，从而阻断GAMs的化学吸引。此外，小胶质细胞和巨噬细胞从前胶质瘤分化为抗肿瘤表型。结论：这些结果为FTY720通过靶向肿瘤微环境中gams -胶质瘤相互作用对胶质瘤的抑制作用提供了新的见解。
Background: Glioblastoma (GBM) is one of the most malignant and aggressive primary brain tumors. The incurability of glioblastoma is heavily influenced by the glioma microenvironment. FTY720, a potent immunosuppressant, has been reported to exert anti-tumor effects in glioblastoma. However, the impact of FTY720 on the glioma microenvironment remains unclear. Methods: We examined the effects of FTY720 on the distribution and polarization of glioma-associated microglia and macrophages (GAMs) in glioma-bearing rats using immunofluorescence staining. qRT-PCR and Western blotting were used to detect the expressions of CXCR4 and MAPK pathway-related signal molecules on microglia in the coculture system. The levels of inflammatory factors were tested via ELISA. Wound healing assay and Matrigel invasion assay were used to determine the migration and invasion of C6 glioma cells. Results: We discovered that FTY720 could inhibit the growth, migration, and invasion of glioma by targeting GAMs to impede their effect on glioma cells. Simultaneously, FTY720 could block the chemoattraction of GAMs by inhibiting MAPK-mediated secretion of IL-6 through increased internalization of CXCR4. Moreover, microglia and macrophages are polarized from pro-glioma to an anti-tumor phenotype. Conclusion: These results provide novel insights into the inhibitory effects of FTY720 on glioma by targeting GAMs–glioma interaction in the tumor microenvironment.