Autocrine sphingosine-1-phosphate fuels growth and stemness in glioblastoma stem cells

Sphingosine-1-phosphate (S1P) is an onco-promoter lipid that, after interaction with specific membrane receptors, acts as a key regulator of growth, invasion, and therapy-resistance of different tumors, including human glioblastomas (GBMs). These are the most common and lethal primary brain cancer in adults, exhibiting a dismal prognosis, despite diverse therapeutic approaches. Accumulating reports suggest that human GBMs contain glioblastoma stem cells (GSCs), a small subpopulation of cells determinant in tumor growth, and malignant progression. Little is known about the role of S1P in GSCs. Using GSCs derived from human GBM specimens with different proliferative index and stemness marker expression, we investigated the possible role of S1P in the proliferative and stemness properties of GSCs. Metabolic studies demonstrated that GSCs can rapidly export newly synthesized S1P, this process being enhanced in fast proliferating cells. Released S1P levels reached nM concentrations in response to increased extracellular sphingosine. Moreover, EGF and bFGF, recognized autocrine factors in GSC, potentiated the constitutive capacity of GSCs to secrete S1P, suggesting that cooperation between S1P and these growth factors is of relevance in GSC maintenance and proliferation. Of relevance, we then found that S1P is able to act as a proliferative and pro-stemness autocrine factor for GSCs, promoting both cell cycle progression and stemness phenotypic profile, in a receptor-dependent fashion. Overall, our results suggest that the GSC population is critically modulated by microenvironmental S1P, that acts as an autocrine signal to maintain a pro-stemness microenvironment and favoring GSC survival, proliferation and maintenance of stem properties. These findings could open novel opportunities for the development of effective treatments for GBMs.