Mesenchymal Differentiation Mediated by NF-κB Promotes Radiation Resistance in Glioblastoma

Bhat, Krishna; Balasubramaniyan, Veerakumar; Vaillant, Brian; Ezhilarasan, Ravesanker; Hummelink, Karlijn; Hollingsworth, Faith; Wani, Khalida; Heathcock, Lindsey; James, Johanna D.; Goodman, Lindsey D.; Conroy, Siobhan; Long, Lihong; Lelic, Nina; Wang, Shuzhen; Gumin, Joy; Raj, Divya; Kodama, Yoshinori; Raghunathan, Aditya; Olar, Adriana; Joshi, Kusum; Pelloski, Christopher E.; Heimberger, Amy B.; Kim, Se Hoon; Cahill, Daniel P.; Rao, Ganesh; Dunnen, Wilfred F. A. den; Boddeke, Hendrikus; Phillips, Heidi S.; Nakano, ﻿Ichiro; Lang, Frederick F.; Colman, Howard; Sulman, Erik P.; Aldape, Kenneth

doi:10.1016/j.ccr.2013.08.001

Cited by 915 publications

(1,269 citation statements)

References 55 publications

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“…In parallel, some studies suggested that there are also different subtypes of GSCs and identified two different subtypes of GSC: proneural type and mesenchymal type [82][83][84]. In the studies of Mao et al [82] and Bhat et al [83], Olig2 is recognised as a marker of proneural GSC. Our results are consistent with these data.…”

Section: Discussionmentioning

confidence: 98%

Identification of OLIG2 as the most specific glioblastoma stem cell marker starting from comparative analysis of data from similar DNA chip microarray platforms

et al. 2014

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Despite advances in surgical and adjuvant treatments, overall survival of glioblastoma (GBM) patients remains poor. The cancer stem cell concept suggests that a rare stem cell population, called glioma stem cells (GSCs), has high ability to self-renewal leading to recurrence in GBM. The identification of specific markers of GSCs would provide a powerful tool to detect and to characterise them in order to develop targeted therapies. We carried out a comparative analysis based on the identification of inter-study concordances to identify the genes that exhibit at best differential levels of expression between GSC-enriched cell cultures and differentiated tumour cell cultures from independent studies using DNA chip microarray technologies. We finally studied the protein expression of the marker we considered the most specific by immunohistochemistry and semi-quantitative analysis on a retrospective series of 18 GBMs. Of the selected studies, 32 genes were retained. Among them, eight genes were identified to be overexpressed in GSC-enriched cultures compared to differentiated tumour cell cultures. Finally, among the eight genes, oligodendrocyte lineage transcription factor 2 (OLIG2) was characterised by the most different expression level in the "GSC model" compared to the "differentiated tumour cells model". Our approach suggests that OLIG2 is the most specific GSC marker; additional investigations with careful considerations about methodology and strategies of validation are, however, mandatory.

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Section: Discussionmentioning

confidence: 98%

Identification of OLIG2 as the most specific glioblastoma stem cell marker starting from comparative analysis of data from similar DNA chip microarray platforms

et al. 2014

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“…2 B, D, and G), experimentally discerning the molecular basis of miR-218-mediated chemoresistance in mesenchymal and proneural subtypes is challenging. Bhat et al (29) recently have shown that brain tumor cells grown as GSCs acquire proneural properties at both the genomic and epigenomic level. Most importantly, even GSCs derived from tumors with an intermediate to high mesenchymal gene signature shift toward the proneural phenotype (29).…”

Section: Resultsmentioning

confidence: 99%

miR-218 opposes a critical RTK-HIF pathway in mesenchymal glioblastoma

Mathew

Skuli

Mucaj

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Glioblastoma multiforme (GBM) and the mesenchymal GBM subtype in particular are highly malignant tumors that frequently exhibit regions of severe hypoxia and necrosis. Because these features correlate with poor prognosis, we investigated microRNAs whose expression might regulate hypoxic GBM cell survival and growth. We determined that the expression of microRNA-218 (miR-218) is decreased significantly in highly necrotic mesenchymal GBM, and orthotopic tumor studies revealed that reduced miR-218 levels confer GBM resistance to chemotherapy. Importantly, miR-218 targets multiple components of receptor tyrosine kinase (RTK) signaling pathways, and miR-218 repression increases the abundance and activity of multiple RTK effectors. This elevated RTK signaling also promotes the activation of hypoxia-inducible factor (HIF), most notably HIF2α. We further show that RTK-mediated HIF2α regulation is JNK dependent, via jun proto-oncogene. Collectively, our results identify an miR-218-RTK-HIF2α signaling axis that promotes GBM cell survival and tumor angiogenesis, particularly in necrotic mesenchymal tumors.

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“…Recent work indicates that mesenchymally shifted cells are more radioresistant (32). Given that therapeutic radiation is given in fractions over a period of days, a radiation-induced mesenchymal shift may represent an important mechanism of resistance to fractionated therapy, with important consequences for optimal design of radiation schedules.…”

Section: Discussionmentioning

confidence: 99%

In vivo radiation response of proneural glioma characterized by protective p53 transcriptional program and proneural-mesenchymal shift

Halliday

Helmy

Pattwell

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

156

161

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Significance Glioblastoma is one of the most radio-resistant tumors, and the mechanisms of radioresistance are intensely studied. Here, we use a mouse model of proneural glioma to evaluate in vivo radiation-induced gene expression regulation at both the translational and transcriptional levels. We found that p53 and E2F are major regulators of the in vivo radiation response, and that there is little contribution from translational regulation, in contrast to previous in vitro reports. We also found that radiation induces a rapid shift in subtype from proneural to mesenchymal, which may have important implications for attempts to tailor targeted therapy regimens to tumor subtype.

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Mesenchymal Differentiation Mediated by NF-κB Promotes Radiation Resistance in Glioblastoma

Cited by 915 publications

References 55 publications

Identification of OLIG2 as the most specific glioblastoma stem cell marker starting from comparative analysis of data from similar DNA chip microarray platforms

Identification of OLIG2 as the most specific glioblastoma stem cell marker starting from comparative analysis of data from similar DNA chip microarray platforms

miR-218 opposes a critical RTK-HIF pathway in mesenchymal glioblastoma

In vivo radiation response of proneural glioma characterized by protective p53 transcriptional program and proneural-mesenchymal shift

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