Glioma-associated Cytomegalovirus Mediates Subversion of the Monocyte Lineage to a Tumor Propagating Phenotype

Overview

Journal Clin Cancer Res

Specialty Oncology

Date 2011 Apr 15

PMID 21490182

Citations 80

Authors

Kristine Dziurzynski

Jun Wei

Wei Qiao

Mustafa Aziz Hatiboglu

Ling-Yuan Kong

Adam Wu

Yongtao Wang

Daniel Cahill

Nicholas Levine

Sujit Prabhu

Ganesh Rao

Raymond Sawaya

Amy B Heimberger

Affiliations

Soon will be listed here.

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.

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