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.
Copyright © 2013 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Basic Helix-Loop-Helix Transcription Factors / genetics
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Basic Helix-Loop-Helix Transcription Factors / metabolism
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Cell Differentiation / genetics
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Cluster Analysis
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DNA Methylation
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Disease Models, Animal
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Epigenesis, Genetic
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Gene Expression Profiling
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Gene Expression Regulation, Neoplastic
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Glioblastoma / genetics*
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Glioblastoma / metabolism*
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Glioblastoma / mortality
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Humans
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Hyaluronan Receptors / genetics
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Hyaluronan Receptors / metabolism
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Mice
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NF-kappa B / genetics*
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NF-kappa B / metabolism*
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism
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Oligodendrocyte Transcription Factor 2
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Prognosis
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Radiation Tolerance / genetics*
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Signal Transduction
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Transcriptome
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Tumor Necrosis Factor-alpha / pharmacology
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Xenograft Model Antitumor Assays
Substances
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Basic Helix-Loop-Helix Transcription Factors
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Hyaluronan Receptors
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NF-kappa B
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Nerve Tissue Proteins
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OLIG2 protein, human
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Oligodendrocyte Transcription Factor 2
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Tumor Necrosis Factor-alpha