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PMID: 21490182 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Clinical cancer research : an official journal of the American Association for Cancer Research ·Vol. 17 ·No. 14 ·2011-07-15 ·Pages 4642-9

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

Abstract

Cytomegalovirus (CMV) has been ubiquitously detected within high-grade gliomas, but its role in gliomagenesis has not been fully elicited. 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. 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. CMV triggers a feedforward mechanism of gliomagenesis by inducing tumor-supportive monocytes.

MeSH Terms
Brain Neoplasms/immunology,metabolism,virology Cell Line, Tumor Cell Lineage Cell Movement/immunology Cytomegalovirus/genetics,immunology,metabolism Cytomegalovirus Infections/immunology,metabolism Gene Expression Regulation, Viral Glioblastoma/immunology,metabolism,virology HL-60 Cells Humans Immunologic Factors/pharmacology Interleukin-10/pharmacology Monocytes/drug effects,immunology,virology Neoplastic Stem Cells/metabolism,virology Phenotype
Chemicals
Immunologic Factors Interleukin-10
Authors & Affiliations
13 authors, click to expand affiliations / ORCID
Dziurzynski Kristine
Departments of Neurosurgery and Biostatistics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
Wei Jun
Qiao Wei
Hatiboglu Mustafa Aziz
Kong Ling-Yuan
Wu Adam
Wang Yongtao
Cahill Daniel
Levine Nicholas
Prabhu Sujit
Rao Ganesh
Sawaya Raymond
Heimberger Amy B
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Article Info
Journal
Clinical cancer research : an official journal of the American Association for Cancer Research
Abbr.
Clin Cancer Res
ISSN
1557-3265
DOI
10.1158/1078-0432.CCR-11-0414
Published
2011-07-15
Epub
2011-00-13
Pages
4642-9
Language
English
Region
United States
NLM ID
9502500
PMCID
PMC3139801
Subset
IM
Grants
NCI NIH HHS · R01 CA120813 · United States
NCI NIH HHS · R01 CA120813-04 · United States
NCI NIH HHS · 5P50 CA127001-03 · United States
NCI NIH HHS · P50 CA127001-03 · United States
NCI NIH HHS · P50 CA127001 · United States
NCI NIH HHS · CA120813--04 · United States
Corrections
CommentIn
PMID: 21632859
External Links
PubMed source DOI: 10.1158/1078-0432.CCR-11-0414 PMC Full Text View journal details
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