Inhibition of CXCL12/CXCR4 autocrine/paracrine loop reduces viability of human glioblastoma stem-like cells affecting self-renewal activity

Toxicology. 2013 Dec 15;314(2-3):209-20. doi: 10.1016/j.tox.2013.10.003. Epub 2013 Oct 21.


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.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autocrine Communication / drug effects
  • Autocrine Communication / physiology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Cell Survival / physiology
  • Chemokine CXCL12 / antagonists & inhibitors
  • Chemokine CXCL12 / biosynthesis*
  • Down-Regulation / drug effects
  • Down-Regulation / physiology
  • Glioblastoma / drug therapy
  • Glioblastoma / metabolism*
  • Glioblastoma / pathology
  • Heterocyclic Compounds / pharmacology
  • Humans
  • Mice, SCID
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / metabolism*
  • Paracrine Communication / drug effects
  • Paracrine Communication / physiology*
  • Receptors, CXCR4 / antagonists & inhibitors
  • Receptors, CXCR4 / biosynthesis*


  • CXCL12 protein, human
  • CXCR4 protein, human
  • Chemokine CXCL12
  • Heterocyclic Compounds
  • Receptors, CXCR4
  • plerixafor