Sphingosine -1-phosphate in the tumor niche promotes glioblastoma malignancy

Glioblastoma (GBM) is the most frequent and lethal brain tumor, and is characterized by not only the presence of cancer cells but also a considerable amount of parenchymal cells. Among them, microglia and endothelial cells are recognized as crucial for both tumor growth and spread. However, the signals regulating the interplay between different cells in the GBM niche are little known. The sphingolipid metabolite sphingosine-1-phosphate (S1P) has emerged as a crucial factor in promoting GBM growth, invasion, and drug-resistance, through interaction with its specific receptors. Notwithstanding, its cellular origin in the GBM niche remains only partially known. In this study we investigated the capacity of microglia and endothelial cells of the GBM niche to act as source and/or target of S1P. We found that different cells of the GBM microenvironment, including GBM-derived tumor cells, stem cells, and endothelial cells, as well as microglia are all able to rapidly synthesize and secrete S1P. Among different cell types, GBM stem cells and GBM-derived endothelial cells were found to be particularly effective in releasing newly synthesized S1P extracellularly. Further experiments revealed that after co-culture, GBM and parenchymal cells exhibit enhanced expression of S1P receptors, and of sphingosine kinase (leading to increased S1P secretion), respectively. In addition, we found that extracellular S1P is able to induce multiple effects on different cells, by promoting growth, stemness and survival of tumor cells, migration and vasculogenesis of endothelial cells, and inflammatory properties of microglia. In conclusion, our data demonstrate that different cell types of the GBM niche and their cross-talk contribute to the S1P enrichment of the GBM microenvironment, where S1P prompts multiple processes which favor GBM progression and malignancy.