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Abstract
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.
Highlights
Glioblastoma (GBM) is one of the most malignant and aggressive primary brain tumors
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 Mitogen-Activated Protein Kinase (MAPK) pathway-related signal molecules on microglia in the coculture system
We discovered that FTY720 could inhibit the growth, migration, and invasion of glioma by targeting Glioma-associated microglia and macrophages (GAMs) to impede their effect on glioma cells
Summary
Glioblastoma (GBM) is one of the most malignant and aggressive primary brain tumors. Glioblastoma, characterized by mortality, is aggressive and invasive, and accounts for up to 50% of primary malignant brain tumors. While most therapeutic strategies have traditionally focused on curbing cancer cell proliferation and invasion, accumulating data suggest that the glioma microenvironment plays an integral role in the development and progression of glioma [6,7,8]. Microglia are resident immune cells of the brain and, together with macrophages, account for ∼30–50% of the infiltrative cells in gliomas, indicating a key role in regulating the glioma microenvironment [9,10,11]. Glioma-associated microglia and macrophages (GAMs) are attracted to tumor cells to promote tumor cell proliferation and invasion, modify the extracellular matrix, and induce an immunosuppressive environment [12]
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