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FTY720 Exerts Anti-Glioma Effects by Regulating the Glioma Microenvironment Through Increased CXCR4 Internalization by Glioma-Associated Microglia.
- Source :
-
Frontiers in immunology [Front Immunol] 2020 Mar 04; Vol. 11, pp. 178. Date of Electronic Publication: 2020 Mar 04 (Print Publication: 2020). - Publication Year :
- 2020
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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.<br /> (Copyright © 2020 Guo, Ji, Xue, Sun, Guo, Cheng and Sun.)
- Subjects :
- Allografts
Animals
Cell Line, Tumor
Cell Movement drug effects
Cell Polarity drug effects
Disease Models, Animal
Glioblastoma pathology
Macrophages drug effects
Macrophages metabolism
Male
Microglia metabolism
Mitogen-Activated Protein Kinases genetics
Mitogen-Activated Protein Kinases metabolism
Rats
Rats, Sprague-Dawley
Rats, Wistar
Receptors, CXCR4 genetics
Signal Transduction drug effects
Antineoplastic Agents administration & dosage
Fingolimod Hydrochloride administration & dosage
Glioblastoma drug therapy
Glioblastoma metabolism
Microglia drug effects
Receptors, CXCR4 metabolism
Tumor Microenvironment drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1664-3224
- Volume :
- 11
- Database :
- MEDLINE
- Journal :
- Frontiers in immunology
- Publication Type :
- Academic Journal
- Accession number :
- 32194542
- Full Text :
- https://doi.org/10.3389/fimmu.2020.00178