FTY720 Exerts Anti-Glioma Effects by Regulating the Glioma Microenvironment Through Increased CXCR4 Internalization by Glioma-Associated Microglia

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.

Exploring Metabolic Adaptations to the Acidic Microenvironment of Osteosarcoma Cells Unveils Sphingosine 1-Phosphate as a Valuable Therapeutic Target

“…FTY720 is FDA approved for the treatment of multiple sclerosis, and it is currently under trial for the treatment of breast carcinoma, glioblastoma and anaplastic astrocytoma (NCT03941743 and NCT02490930). FTY720 has several anticancer effects [ 77 , 78 , 79 , 80 , 81 ] but its activity in OS has not been explored so far. Despite being considered an S1P receptor modulator, FTY720 is also able to induce changes in the enzymes of the sphingolipid pathway, including SPHK1 [ 54 , 55 , 56 ], thus providing an explanation for the reduction of S1P seen in our model.…”

Macrophages/Microglia in the Glioblastoma Tumor Microenvironment

“…FTY720 could inhibit the growth, migration, and invasion of glioma by targeting GAMs to impede their effect on glioma cells, while also potentially blocking the chemoattraction of GAMs by inhibiting the MAPK-mediated secretion of IL-6 through the increased internalization of CXCR4. Microglia and macrophages are polarized from pro-glioma to an anti-tumor phenotype [ 89 ]. Zhang et al showed that GAMs display a continuum of different polarization states between anti-tumorigenic and pro-tumorigenic macrophage phenotypes.…”

Sphingolipid Metabolism in Glioblastoma and Metastatic Brain Tumors: A Review of Sphingomyelinases and Sphingosine-1-Phosphate

“…In long-term usage, this was shown to increase the risk of cancer development [ 158 ]. Subsequent investigations revealed that fingolimod decreased recruitment of macrophages to the brain tumor microenvironment, as well as pushed them toward a proinflammatory (M1) phenotype via C-X-C Motif Chemokine Receptor 4 (CXCR4) internalization [ 159 ]. Outside of the tumor setting, mice without S1P lyase expression had greater microglial activation in the brain.…”