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


Posted on: 04/27/2011

Clin Cancer Res. 2011 Apr 13. [Epub ahead of print]

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

Dziurzynski K, Wei J, Qiao W, Hatiboglu MA, Kong LY, Wu A, Wang Y, Cahill D, Levine NB, Prabhu S, Rao G, Sawaya R, Heimberger AB.

Neurosurgery, UTMDACC.

 

Abstract

PURPOSE: 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 gCSC CMV IL-10 production was determined by ELISA. Human monocytes were stimulated with recombinant CMV IL-10 and levels of expression of p-STAT3, VEGF, TGF-beta, 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 demonstrated a tropism for macrophages (M Phi s)/microglia and CD133+ gCSCs within GBMs. The gCSCs produce CMV IL-10, which induces human monocytes (the precursor to the CNS M Phi s/microglia) to assume an M2 immunosuppressive phenotype (as manifested by down modulation of the major histocompatibility complex and costimulatory molecules) while up regulating immune inhibitory 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 angiogeneic VEGF, immunosuppressive TGF-beta, and enhanced migration of gCSCs.

 

CONCLUSIONS: CMV triggers a feed-forward mechanism of gliomagenesis by inducing tumor-supportive monocytes.

 

 


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