Targeting interleukin 6 signaling suppresses glioma stem cell survival and tumor growth.
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.
Wang
Hui
H
Department of Pharmacology, Duke University Medical Center, Durham, North Carolina, USA.
Lathia
Justin D
JD
Wu
Qiulian
Q
Wang
Jialiang
J
Li
Zhizhong
Z
Heddleston
John M
JM
Eyler
Christine E
CE
Elderbroom
Jennifer
J
Gallagher
Joseph
J
Schuschu
Jesse
J
MacSwords
Jennifer
J
Cao
Yiting
Y
McLendon
Roger E
RE
Wang
Xiao-Fan
XF
Hjelmeland
Anita B
AB
Rich
Jeremy N
JN
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D050822:Cytokine Receptor gp130 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D005910:Glioma / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D006085:Graft Survival / Q000187:drug effects / Q000502:physiology; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D034622:RNA Interference / Q000502:physiology; D034741:RNA, Small Interfering / Q000494:pharmacology; D019947:Receptors, Interleukin-6 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D000093242:Interleukin-6 Inhibitors
D050822:Cytokine Receptor gp130; D006131:Growth Inhibitors; D015850:Interleukin-6; D034741:RNA, Small Interfering; D019947:Receptors, Interleukin-6; D050796:STAT3 Transcription Factor; D000093242:Interleukin-6 Inhibitors