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Autocrine/paracrine sphingosine‐1‐phosphate fuels proliferative and stemness qualities of glioblastoma stem cells
Author(s) -
Marfia Giovanni,
Campanella Rolando,
Navone Stefania Elena,
Vito Clara,
Riccitelli Elena,
Hadi Loubna Abdel,
Bornati Andrea,
Rezende Gisele,
Giussani Paola,
Tringali Cristina,
Viani Paola,
Rampini Paolo,
Alessandri Giulio,
Parati Eugenio,
Riboni Laura
Publication year - 2014
Publication title -
glia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.954
H-Index - 164
eISSN - 1098-1136
pISSN - 0894-1491
DOI - 10.1002/glia.22718
Subject(s) - autocrine signalling , paracrine signalling , biology , stem cell , cancer research , sphingosine , sphingosine 1 phosphate , microbiology and biotechnology , cancer stem cell , glioma , cell culture , receptor , biochemistry , genetics
Accumulating reports suggest that human glioblastoma contains glioma stem‐like cells (GSCs) which act as key determinants driving tumor growth, angiogenesis, and contributing to therapeutic resistance. The proliferative signals involved in GSC proliferation and progression remain unclear. Using GSC lines derived from human glioblastoma specimens with different proliferative index and stemness marker expression, we assessed the hypothesis that sphingosine‐1‐phosphate (S1P) affects the proliferative and stemness properties of GSCs. The results of metabolic studies demonstrated that GSCs rapidly consume newly synthesized ceramide, and export S1P in the extracellular environment, both processes being enhanced in the cells exhibiting high proliferative index and stemness markers. Extracellular S1P levels reached nM concentrations in response to increased extracellular sphingosine. In addition, the presence of EGF and bFGF potentiated the constitutive capacity of GSCs to rapidly secrete newly synthesized S1P, suggesting that cooperation between S1P and these growth factors is of central importance in the maintenance and proliferation of GSCs. We also report for the first time that S1P is able to act as a proliferative and pro‐stemness autocrine factor for GSCs, promoting both their cell cycle progression and stemness phenotypic profile. These results suggest for the first time that the GSC population is critically modulated by microenvironmental S1P, this bioactive lipid acting as an autocrine signal to maintain a pro‐stemness environment and favoring GSC proliferation, survival and stem properties. GLIA 2014;62:1968–1981