Targeting interleukin 6 signaling suppresses glioma stem cell survival and tumor growth

Stem Cells. 2009 Oct;27(10):2393-404. doi: 10.1002/stem.188.


Glioblastomas are the most common and most lethal primary brain tumor. Recent studies implicate an important role for a restricted population of neoplastic cells (glioma stem cells (GSCs)) in glioma maintenance and recurrence. We now demonstrate that GSCs preferentially express two interleukin 6 (IL6) receptors: IL6 receptor alpha (IL6R alpha) and glycoprotein 130 (gp130). Targeting IL6R alpha or IL6 ligand expression in GSCs with the use of short hairpin RNAs (shRNAs) significantly reduces growth and neurosphere formation capacity while increasing apoptosis. Perturbation of IL6 signaling in GSCs attenuates signal transducers and activators of transcription three (STAT3) activation, and small molecule inhibitors of STAT3 potently induce GSC apoptosis. These data indicate that STAT3 is a downstream mediator of prosurvival IL6 signals in GSCs. Targeting of IL6R alpha or IL6 expression in GSCs increases the survival of mice bearing intracranial human glioma xenografts. IL6 is clinically significant because elevated IL6 ligand and receptor expression are associated with poor glioma patient survival. The potential utility of anti-IL6 therapies is demonstrated by decreased growth of subcutaneous human GSC-derived xenografts treated with IL6 antibody. Together, our data indicate that IL6 signaling contributes to glioma malignancy through the promotion of GSC growth and survival, and that targeting IL6 may offer benefit for glioma patients.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / genetics
  • Brain Neoplasms / immunology
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Cell Survival / genetics
  • Cell Survival / immunology
  • Cytokine Receptor gp130 / drug effects
  • Cytokine Receptor gp130 / genetics
  • Cytokine Receptor gp130 / metabolism
  • Glioma / drug therapy*
  • Glioma / genetics
  • Glioma / immunology
  • Graft Survival / drug effects
  • Graft Survival / physiology
  • Growth Inhibitors / pharmacology
  • Humans
  • Interleukin-6 / antagonists & inhibitors*
  • Interleukin-6 / metabolism
  • Mice
  • Mice, Nude
  • Neoplastic Stem Cells / drug effects*
  • Neoplastic Stem Cells / immunology
  • Neoplastic Stem Cells / metabolism
  • RNA Interference / physiology
  • RNA, Small Interfering / pharmacology
  • Receptors, Interleukin-6 / drug effects
  • Receptors, Interleukin-6 / genetics
  • Receptors, Interleukin-6 / metabolism
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Signal Transduction / immunology
  • Transplantation, Heterologous
  • Tumor Cells, Cultured


  • Growth Inhibitors
  • Interleukin-6
  • RNA, Small Interfering
  • Receptors, Interleukin-6
  • STAT3 Transcription Factor
  • Cytokine Receptor gp130