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Cancer Cell. 2013 Sep 9;24(3):331-46. doi: 10.1016/j.ccr.2013.08.001. Epub 2013 Aug 29.

Mesenchymal differentiation mediated by NF-κB promotes radiation resistance in glioblastoma.

Author information

1
Department of Pathology, The University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030, USA.
2
Department of Neuroscience, University of Groningen, University Medical Center Groningen, Groningen, 9713 AV, The Netherlands.
3
Seton Brain and Spine Institute, Austin, TX 78701, USA.
4
Department of Radiation Oncology, The University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030, USA.
5
Deparment of Neurosurgery, Massachusetts General Hospital/Brain Tumor Center, Boston, MA 02114, USA.
6
Department of Neuro-oncology, The University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030, USA.
7
Department of Neurosurgery, The University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030, USA.
8
Division of Pathology, Osaka National Hospital, National Hospital Organization, Chuo-ku, Osaka 540-0006, Japan.
9
Department of Pathology, Henry Ford Hospital, Detroit, MI, 48202, USA.
10
Department of Neurosurgery, The Ohio State University, Columbus, OH 43210, USA.
11
Department of Radiation Oncology, The Ohio State University, Columbus, OH 43210, USA.
12
Department of Pathology, Yonsei University College of Medicine, Seoul, 120-752, Korea.
13
Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, 9700 RB, The Netherlands.
14
Department of Tumor Biology and Angiogenesis, Genentech, Inc., South San Francisco, CA 94080, USA.
15
Department of Neurosurgery, and Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84132, USA.
#
Contributed equally

Abstract

Despite extensive study, few therapeutic targets have been identified for glioblastoma (GBM). Here we show that patient-derived glioma sphere cultures (GSCs) that resemble either the proneural (PN) or mesenchymal (MES) transcriptomal subtypes differ significantly in their biological characteristics. Moreover, we found that a subset of the PN GSCs undergoes differentiation to a MES state in a TNF-α/NF-κB-dependent manner with an associated enrichment of CD44 subpopulations and radioresistant phenotypes. We present data to suggest that the tumor microenvironment cell types such as macrophages/microglia may play an integral role in this process. We further show that the MES signature, CD44 expression, and NF-κB activation correlate with poor radiation response and shorter survival in patients with GBM.

PMID:
23993863
PMCID:
PMC3817560
DOI:
10.1016/j.ccr.2013.08.001
[Indexed for MEDLINE]
Free PMC Article

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