title: Autocrine/paracrine sphingosine-1-phosphate fuels proliferative and stemness qualities of glioblastoma stem cells.
abstract: 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.
authors.affiliation: Laboratory of Experimental Neurosurgery and Cell Therapy, Neurosurgery Unit, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico Milan, University of Milan, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Marfia
authors.forename: Rolando
authors.initials: R
authors.lastname: Campanella
authors.forename: Stefania Elena
authors.initials: SE
authors.lastname: Navone
authors.forename: Clara
authors.initials: C
authors.lastname: Di Vito
authors.forename: Elena
authors.initials: E
authors.lastname: Riccitelli
authors.forename: Loubna Abdel
authors.initials: LA
authors.lastname: Hadi
authors.forename: Andrea
authors.initials: A
authors.lastname: Bornati
authors.forename: Gisele
authors.initials: G
authors.lastname: de Rezende
authors.forename: Paola
authors.initials: P
authors.lastname: Giussani
authors.forename: Cristina
authors.initials: C
authors.lastname: Tringali
authors.forename: Paola
authors.initials: P
authors.lastname: Viani
authors.forename: Paolo
authors.initials: P
authors.lastname: Rampini
authors.forename: Giulio
authors.initials: G
authors.lastname: Alessandri
authors.forename: Eugenio
authors.initials: E
authors.lastname: Parati
authors.forename: Laura
authors.initials: L
authors.lastname: Riboni
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000473:pathology*; D049109:Cell Proliferation / Q000502:physiology*; D002478:Cells, Cultured; D002518:Ceramides / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000494:pharmacology; D045604:Extracellular Fluid / Q000187:drug effects / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D000068876:Fingolimod Hydrochloride; D005909:Glioblastoma / Q000473:pathology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D019394:Ki-67 Antigen / Q000378:metabolism; D008246:Lysophospholipids / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D016513:Mice, SCID; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000502:physiology*; D011409:Propylene Glycols / Q000494:pharmacology; D013107:Sphingolipids / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D002518:Ceramides; D007166:Immunosuppressive Agents; D019394:Ki-67 Antigen; D008246:Lysophospholipids; D011409:Propylene Glycols; D013107:Sphingolipids; D016222:Fibroblast Growth Factor 2; C060506:sphingosine 1-phosphate; D004815:Epidermal Growth Factor; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine
keywords: CD133; ceramide; growth factors; sphingolipid metabolism; stem cell niche