Glioma-Associated Cytomegalovirus Mediates Subversion of the Monocyte Lineage to a Tumor Propagating Phenotype
- 15 July 2011
- journal article
- Published by American Association for Cancer Research (AACR) in Clinical Cancer Research
- Vol. 17 (14), 4642-4649
- https://doi.org/10.1158/1078-0432.ccr-11-0414
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. Clin Cancer Res; 17(14); 4642–9. ©2011 AACR.Other Versions
This publication has 52 references indexed in Scilit:
- Glioma cancer stem cells induce immunosuppressive macrophages/microgliaNeuro-Oncology, 2010
- The PTEN-regulating microRNA miR-26a is amplified in high-grade glioma and facilitates gliomagenesis in vivoGenes & Development, 2009
- Malignant Astrocytomas Originate from Neural Stem/Progenitor Cells in a Somatic Tumor Suppressor Mouse ModelCancer Cell, 2009
- Neonatal Neural Progenitor Cells and Their Neuronal and Glial Cell Derivatives Are Fully Permissive for Human Cytomegalovirus InfectionJournal of Virology, 2008
- Stimulation of B lymphocytes by cmvIL-10 but not LAcmvIL-10Virology, 2008
- Detection of human cytomegalovirus in different histological types of gliomasActa Neuropathologica, 2008
- Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironmentNature Reviews Immunology, 2007
- Glioma stem cells promote radioresistance by preferential activation of the DNA damage responseNature, 2006
- Human cytomegalovirus-encoded chemokine receptor US28 promotes tumorigenesisProceedings of the National Academy of Sciences of the United States of America, 2006
- The STATs of cancer — new molecular targets come of ageNature Reviews Cancer, 2004