Investigating the in vivo effects of dexamethasone using a human disease relevant mouse model of glioblastoma

Purpose: Glioblastoma (GBM) is the most common and malignant primary brain tumor overall. Standard therapy includes dexamethasone for symptom management prior to surgical resection and DNA damaging therapy (temozolomide, radiation); and in many cases maintenance on dexamethasone through post-operative radiation therapy. It is not known how dexamethasone works in glioma or if it influences the response to DNA damaging therapy. The goal of our study was to investigate the effects of dexamethasone in glioma and elucidate possible mechanisms of action using a PDGF-driven mouse model of GBM.

Methods: We treated glioma-bearing mice with 10mg/kg/day of dexamethasone for 3 days and collected tissue for immunohistochemical and microarray analysis. In vitro studies were performed using primary glioma cultures to validate in vivo findings.

Results: We found that the majority of the differentially expressed genes were down-regulated by dexamethasone and were involved in cell cycle proliferation; which was confirmed by PCNA and Ki67 immunohistochemistry. When these genes were analyzed in The Cancer Genome Atlas (TCGA) GBM data set, we found that high expression of the genes down-regulated by dexamethasone predicts a significantly longer survival compared to tumors with lower levels. Studies of glioma cultures treated in vitroÊsuggest that dexamethasone may work indirectly through the tumor microenvironment; and microarray analysis of tumor and tumor-associated microglial cells provides insight into possible mechanisms of action.

Conclusion: Our data suggests that dexamethasoneÊinhibits tumor cell proliferation, possibly through a tumor-microenvironment interaction. TCGA analysis suggests that down-regulation of our dexamethasone-induced gene set may have an adverse effect on survival.Ê It is possible that a decrease in tumor cell proliferation may decrease the efficacy of antineoplastic therapy that is most toxic to proliferating cells.Ê This study confirms the importance of defining the mechanism of how dexamethasone affects tumor and stromal cells in glioma.