Reduced glioma growth following dexamethasone or anti-angiopoietin 2 treatment.
All patients with glioblastoma, the most aggressive and common form of brain cancer, develop cerebral edema. This complication is routinely treated with dexamethasone, a steroidal anti-inflammatory drug whose effects on brain tumors are not fully understood. Here we show that dexamethasone can reduce glioma growth in mice, even though it depletes infiltrating T cells with potential antitumor activity. More precisely, T cells with helper or cytotoxic function were sensitive to dexamethasone, but not those that were negative for the CD4 and CD8 molecules, including gammadelta and natural killer (NK) T cells. The antineoplastic effect of dexamethasone was indirect, as it did not meaningfully affect the growth and gene expression profile of glioma cells in vitro. In contrast, hundreds of dexamethasone-modulated genes, notably angiopoietin 2 (Angpt2), were identified in cultured cerebral endothelial cells by microarray analysis. The ability of dexamethasone to attenuate Angpt2 expression was confirmed in vitro and in vivo. Selective neutralization of Angpt2 using a peptide-Fc fusion protein reduced glioma growth and vascular enlargement to a greater extent than dexamethasone, without affecting T cell infiltration. In conclusion, this study suggests a mechanism by which dexamethasone can slow glioma growth, providing a new therapeutic target for malignant brain tumors.
Villeneuve
Jérôme
J
Department of Oncology and Molecular Endocrinology, Laval University Hospital Research Center, Québec City, Québec, Canada.
Galarneau
Hugo
H
Beaudet
Marie-Josée
MJ
Tremblay
Pierrot
P
Chernomoretz
Ariel
A
Vallières
Luc
L
D042702:Angiopoietin-2 / Q000037:antagonists & inhibitors*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects; D005910:Glioma / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000187:drug effects
D042702:Angiopoietin-2; D000893:Anti-Inflammatory Agents; D011993:Recombinant Fusion Proteins; D003907:Dexamethasone