Targeting Interleukin 6 Signaling Suppresses Glioma Stem Cell Survival and Tumor Growth§

Authors


  • Author contributions: H.W.: Financial support conception and design, collection and/or assembly of data, data analysis and interpretation, manuscript writing; J.D.L.: Financial support, conception and design, collection and/or assembly of data; Q.W.: Collection and/or assembly of data; J.W.: Financial support, collection and/or assembly of data; Z.L.: Conception and design, collection and/or assembly of data; J.M.H.: Collection and/or assembly of data; C.E.E.: Collection and/or assembly of data; J.E.: Collection and/or assembly of data; J.G.: Collection and/or assembly of data; J.S.: Collection and/or assembly of data; J.M.: Collection and/or assembly of data; Y.C.: Financial support, collection and/or assembly of data; R.E.M.: Provision of study materials or patients, collection and/or assembly of data; X.-F.W.: Financial support, conception and design; A.B.H.: Financial support, conception and design, collection and/or assembly of data, data analysis and interpretation, manuscript writing; J.N.R.: Financial support, conception and design, manuscript writing, final approval of manuscript.

  • Disclosure of potential conflicts of interest is found at the end of this article.

  • §

    First published online in STEM CELLS EXPRESS August 5, 2009.

Abstract

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 (IL6Rα) and glycoprotein 130 (gp130). Targeting IL6Rα 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 IL6Rα 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. STEM CELLS 2009;27:2393–2404

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