ACQUIRED ALTERATIONS OF SPHINGOSINE-1-PHOSPHATE METABOLISM CONFER STEMNESS AND DRUG RESISTANCE PROPERTIES ON GLIOBLASTOMA MULTIFORME: A NEW POTENTIAL TARGET FOR A COMBINED APPROACH TO TREAT BRAIN CANCER

The eradication of glioblastoma multiforme (GBM) (WHO grade 4) remains a tremendous clinical challenge in human oncology. Indeed, this tumor accounts for the most common, aggressive and lethal primary brain cancer in adults, exhibiting a dismal prognosis, despite extensive surgical resection and adjuvant radio- and chemo-therapy. The finding that GBM contains functional subsets of cells with stem-like properties named glioblastoma stem cells (GSCs) has opened up novel opportunities and promises for the development of new therapies for this devastating cancer. GSCs are self-renewing, multipotent cells, with the capacity to establish and maintain glioma tumors at the clonal level, leading to the hypothesis that they are tumor-initiating cells. Moreover, these rare subpopulations of cells possess an elevated proliferative potential, and intrinsic resistance to therapy, being thus considered a key determinant driving tumor growth, and relapse after resection and therapy. In serum free culture conditions, GSCs form neurospheres. free-floating cell aggregates with a spheroid morphology. These neurospheres preserve many of the important characteristics of the parent tumor, as cell heterogeneity and the ability to drive the parent tumor’s cell invasiveness, when transplanted in murine brain. In addition, GSCs possess the capacities to give rise to a heterogeneous population of cells such as endothelial cells (glioblastoma endothelial cells, GECs) which may directly participate in the vascularization, a critical step in tumors, particularly in malignant GBM, one of the most vascularized/angiogenic tumor described. Moreover, it has been observed that microvasculature structures are the regions responsible for the localization and the maintenance of GSCs. Different molecules, including lipid mediators appear to play a key role in the GBM microenvironment. Among lipid mediators involved in GSC properties, ceramide (Cer) and sphingosine-1-phosphate (S1P) has recently emerged as key signals, able to control growth, invasion, and therapy resistance in various human cancers, including GBMs. Of relevance, the presence of S1P in both glioma cell lines and human gliomas is critical for tumor cell proliferation and survival, a down-regulation of sphingosine kinase 1 (SK1) suppressed growth of human GBM cells and xenografts, and a higher expression of S1P receptor 1 (S1PR1) in GBM has been correlated with poor prognosis. However, little is known on the role of Cer and S1P in GSCs. Recent studies reported that S1P acts as an invasive signal in GSCs, and that the inhibition of SKs, or the administration of a S1PR antagonist, results in GSC death. Very recently it was reported that GSCs derived from U87GBM cells, and those isolated from a human GBM specimen can release S1P extracellularly, and that S1P acts as a first messenger to enhance GSC chemoresistance to Temozolomide. In GSC invasiveness and chemoresistance very little is known about autocrine machinery controlling GSC proliferation and particularly on the significance of S1P in these events. In order to expand previous investigation on S1P and to better understand its role on GSC activity and chemoresistance in this project I focused on the pivotal role of S1P on GSC stemness properties.