Dexamethasone-mediated oncogenicity in vitro and in an animal model of glioblastoma.

Lüdi, Markus; Singh, Sanjay K; Mosley, Jennifer C; Hassan, Islam S A; Hatami, Masumeh; Gumin, Joy; Andereggen, Lukas; Sulman, Erik P; Lang, Frederick F; Stüber, Frank; Fuller, Gregory N; Colen, Rivka R; Zinn, Pascal O (2018). Dexamethasone-mediated oncogenicity in vitro and in an animal model of glioblastoma. Journal of neurosurgery, 129(6), pp. 1446-1455. American Association of Neurological Surgeons 10.3171/2017.7.JNS17668

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OBJECTIVE Dexamethasone, 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. METHODS Expression 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). RESULTS The 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. CONCLUSIONS The 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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Intensive Care, Emergency Medicine and Anaesthesiology (DINA) > Clinic and Policlinic for Anaesthesiology and Pain Therapy

UniBE Contributor:

Lüdi, Markus and Stüber, Frank

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0022-3085

Publisher:

American Association of Neurological Surgeons

Language:

English

Submitter:

Jeannie Wurz

Date Deposited:

22 Mar 2018 14:52

Last Modified:

05 Jan 2019 01:30

Publisher DOI:

10.3171/2017.7.JNS17668

PubMed ID:

29328002

Uncontrolled Keywords:

APC = allophycocyanin FACS = fluorescence-activated cell sorting FDR = false discovery rate FSC-A = forward scatter absorption GBM = glioblastoma GSC = glioblastoma stem cell GSEA = gene set enrichment analysis IPA = Ingenuity Pathway Analysis TCGA = The Cancer Genome Atlas angiogenesis dexamethasone glioblastoma glioblastoma stem cells invasion miRNA = microRNA oncology proliferation

BORIS DOI:

10.7892/boris.113488

URI:

https://boris.unibe.ch/id/eprint/113488

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