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Clin Cancer Res. 2011 Jul 15;17(14):4642-9. doi: 10.1158/1078-0432.CCR-11-0414. Epub 2011 Apr 13.

Glioma-associated cytomegalovirus mediates subversion of the monocyte lineage to a tumor propagating phenotype.

Author information

1
Departments of Neurosurgery and Biostatistics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.

Abstract

PURPOSE:

Cytomegalovirus (CMV) has been ubiquitously detected within high-grade gliomas, but its role in gliomagenesis has not been fully elicited.

EXPERIMENTAL DESIGN:

Glioblastoma multiforme (GBM) tumors were analyzed by flow cytometry to determine CMV antigen expression within various glioma-associated immune populations. The glioma cancer stem cell (gCSC) CMV interleukin (IL)-10 production was determined by ELISA. Human monocytes were stimulated with recombinant CMV IL-10 and levels of expression of p-STAT3, VEGF (vascular endothelial growth factor), TGF-β, viral IE1, and pp65 were determined by flow cytometry. The influence of CMV IL-10-treated monocytes on gCSC biology was ascertained by functional assays.

RESULTS:

CMV showed a tropism for macrophages (MΦ)/microglia and CD133+ gCSCs within GBMs. The gCSCs produce CMV IL-10, which induces human monocytes (the precursor to the central nervous system MΦs/microglia) to assume an M2 immunosuppressive phenotype (as manifested by downmodulation of the major histocompatibility complex and costimulatory molecules) while upregulating immunoinhibitory B7-H1. CMV IL-10 also induces expression of viral IE1, a modulator of viral replication and transcription in the monocytes. Finally, the CMV IL-10-treated monocytes produced angiogenic VEGF, immunosuppressive TGF-β, and enhanced migration of gCSCs.

CONCLUSIONS:

CMV triggers a feedforward mechanism of gliomagenesis by inducing tumor-supportive monocytes.

PMID:
21490182
PMCID:
PMC3139801
DOI:
10.1158/1078-0432.CCR-11-0414
[Indexed for MEDLINE]
Free PMC Article
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