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Dexamethasone-mediated oncogenicity in vitro and in an animal model of glioblastoma
- Source :
- Journal of Neurosurgery. 129:1446-1455
- Publication Year :
- 2018
- Publisher :
- Journal of Neurosurgery Publishing Group (JNSPG), 2018.
-
Abstract
- OBJECTIVEDexamethasone, a known regulator of mesenchymal programming in glioblastoma (GBM), is routinely used to manage edema in GBM patients. Dexamethasone also activates the expression of genes, such as CEBPB, in GBM stem cells (GSCs). However, the drug’s impact on invasion, proliferation, and angiogenesis in GBM remains unclear. To determine whether dexamethasone induces invasion, proliferation, and angiogenesis in GBM, the authors investigated the drug’s impact in vitro, in vivo, and in clinical information derived from The Cancer Genome Atlas (TCGA) cohort.METHODSExpression profiles of patients from the TCGA cohort with mesenchymal GBM (n = 155) were compared with patients with proneural GBM by comparative marker selection. To obtain robust data, GSCs with IDH1 wild-type (GSC3) and with IDH1 mutant (GSC6) status were exposed to dexamethasone in vitro and in vivo and analyzed for invasion (Boyden chamber, human-specific nucleolin), proliferation (Ki-67), and angiogenesis (CD31). Ex vivo tumor cells from dexamethasone-treated and control mice were isolated by fluorescence activated cell sorting and profiled using Affymetrix chips for mRNA (HTA 2.0) and microRNAs (miRNA 4.0). A pathway analysis was performed to identify a dexamethasone-regulated gene signature, and its relationship with overall survival (OS) was assessed using Kaplan-Meier analysis in the entire GBM TCGA cohort (n = 520).RESULTSThe mesenchymal subgroup, when compared with the proneural subgroup, had significant upregulation of a dexamethasone-regulated gene network, as well as canonical pathways of proliferation, invasion, and angiogenesis. Dexamethasone-treated GSC3 demonstrated a significant increase in invasion, both in vitro and in vivo, whereas GSC6 demonstrated a modest increase. Furthermore, dexamethasone treatment of both GSC3 and GSC6 lines resulted in significantly elevated cell proliferation and angiogenesis in vivo. Patients with mesenchymal GBM had significant upregulation of dexamethasone-regulated pathways when compared with patients with proneural GBM. A prognostic (p = 0.0007) 33-gene signature was derived from the ex vivo expression profile analyses and used to dichotomize the entire TCGA cohort by high (median OS 12.65 months) or low (median OS 14.91 months) dexamethasone signature.CONCLUSIONSThe authors present evidence that furthers the understanding of the complex effects of dexamethasone on biological characteristics of GBM. The results suggest that the drug increases invasion, proliferation, and angiogenesis in human GSC-derived orthotopic tumors, potentially worsening GBM patients’ prognoses. The authors believe that careful investigation is needed to determine how to minimize these deleterious dexamethasone-associated side effects in GBM.
- Subjects :
- 0301 basic medicine
CD31
Angiogenesis
Dexamethasone
Mice
03 medical and health sciences
0302 clinical medicine
In vivo
microRNA
Animals
Humans
Medicine
Neoplasm Invasiveness
Cell Proliferation
Brain Neoplasms
business.industry
Gene Expression Profiling
Mesenchymal stem cell
General Medicine
Gene signature
Gene Expression Regulation, Neoplastic
Disease Models, Animal
030104 developmental biology
030220 oncology & carcinogenesis
Neoplastic Stem Cells
Cancer research
Stem cell
Glioblastoma
business
Ex vivo
Subjects
Details
- ISSN :
- 19330693 and 00223085
- Volume :
- 129
- Database :
- OpenAIRE
- Journal :
- Journal of Neurosurgery
- Accession number :
- edsair.doi.dedup.....72d89aa6282afabaf3304e85c3ce24fe