title: Inhibition of CXCL12/CXCR4 autocrine/paracrine loop reduces viability of human glioblastoma stem-like cells affecting self-renewal activity.
abstract: Cancer stem cells (CSCs) or tumor initiating cells (TICs) drive glioblastoma (GBM) development, invasiveness and drug resistance. Distinct molecular pathways might regulate CSC biology as compared to cells in the bulk tumor mass, representing potential therapeutic targets. Chemokine CXCL12 and its receptor CXCR4 control proliferation, invasion and angiogenesis in GBM cell lines and primary cultures, but little is known about their activity in GBM CSCs. We demonstrate that CSCs, isolated from five human GBMs, express CXCR4 and release CXCL12 in vitro, although different levels of expression and secretion were observed in individual cultures, as expected for the heterogeneity of GBMs. CXCL12 treatment induced Akt-mediated significant pro-survival and self-renewal activities, while proliferation was induced at low extent. The role of CXCR4 signaling in CSC survival and self-renewal was further demonstrated using the CXCR4 antagonist AMD3100 that reduced self-renewal and survival with greater efficacy in the cultures that released higher CXCL12 amounts. The specificity of CXCL12 in sustaining CSC survival was demonstrated by the lack of AMD3100-dependent inhibition of viability in differentiated cells derived from the same GBMs. These findings, although performed on a limited number of tumor samples, suggest that the CXCL12/CXCR4 interaction mediates survival and self-renewal in GBM CSCs with high selectivity, thus emerging as a candidate system responsible for maintenance of cancer progenitors, and providing survival benefits to the tumor.
authors.affiliation: Section of Pharmacology, Department of Internal Medicine, University of Genova, Viale Benedetto XV, 2, 16132 Genova, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Gatti
authors.forename: Alessandra
authors.initials: A
authors.lastname: Pattarozzi
authors.forename: Adriana
authors.initials: A
authors.lastname: Bajetto
authors.forename: Roberto
authors.initials: R
authors.lastname: Würth
authors.forename: Antonio
authors.initials: A
authors.lastname: Daga
authors.forename: Pietro
authors.initials: P
authors.lastname: Fiaschi
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Zona
authors.forename: Tullio
authors.initials: T
authors.lastname: Florio
authors.forename: Federica
authors.initials: F
authors.lastname: Barbieri
mesh_terms: D000818:Animals; D019898:Autocrine Communication / Q000187:drug effects / Q000502:physiology*; D001596:Benzylamines; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D054377:Chemokine CXCL12 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D000080027:Cyclams; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D006571:Heterocyclic Compounds / Q000494:pharmacology; D006801:Humans; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D019899:Paracrine Communication / Q000187:drug effects / Q000502:physiology*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*
chemical_list: D001596:Benzylamines; C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D000080027:Cyclams; D006571:Heterocyclic Compounds; D019718:Receptors, CXCR4; C088327:plerixafor
keywords: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; 4′,6-diamidino-2-phenylindole; Akt; BM; C-X-C motif ligand 12; C-X-C motif receptor 4; CM; CSC; CXCL12; CXCR4; Cancer stem cells; DAPI; EGF; ERK1/2; GBM; Glioblastoma; Intracellular signaling; MTT; TIC; bFGF; basal medium (non-containing growth factors); basic fibroblast growth factor; cancer stem cell; complete medium (supplemented with EGF and bFGF); epidermal growth factor; extracellular regulated kinase 1/2; glioblastoma; protein kinase B; tumor initiating cell