title: Glioma-associated cytomegalovirus mediates subversion of the monocyte lineage to a tumor propagating phenotype.
abstract: OBJECTIVE
  Cytomegalovirus (CMV) has been ubiquitously detected within high-grade gliomas, but its role in gliomagenesis has not been fully elicited.
  
  
  METHODS
  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.
authors.affiliation: Departments of Neurosurgery and Biostatistics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Kristine
authors.initials: K
authors.lastname: Dziurzynski
authors.forename: Jun
authors.initials: J
authors.lastname: Wei
authors.forename: Wei
authors.initials: W
authors.lastname: Qiao
authors.forename: Mustafa Aziz
authors.initials: MA
authors.lastname: Hatiboglu
authors.forename: Ling-Yuan
authors.initials: LY
authors.lastname: Kong
authors.forename: Adam
authors.initials: A
authors.lastname: Wu
authors.forename: Yongtao
authors.initials: Y
authors.lastname: Wang
authors.forename: Daniel
authors.initials: D
authors.lastname: Cahill
authors.forename: Nicholas
authors.initials: N
authors.lastname: Levine
authors.forename: Sujit
authors.initials: S
authors.lastname: Prabhu
authors.forename: Ganesh
authors.initials: G
authors.lastname: Rao
authors.forename: Raymond
authors.initials: R
authors.lastname: Sawaya
authors.forename: Amy B
authors.initials: AB
authors.lastname: Heimberger
mesh_terms: D001932:Brain Neoplasms / Q000276:immunology* / Q000378:metabolism* / Q000821:virology*; D045744:Cell Line, Tumor; D019070:Cell Lineage; D002465:Cell Movement / Q000276:immunology; D003587:Cytomegalovirus / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D003586:Cytomegalovirus Infections / Q000276:immunology / Q000378:metabolism; D015967:Gene Expression Regulation, Viral; D005909:Glioblastoma / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D018922:HL-60 Cells; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology; D016753:Interleukin-10 / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects / Q000276:immunology* / Q000821:virology; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000821:virology; D010641:Phenotype
chemical_list: D007155:Immunologic Factors; D016753:Interleukin-10