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.
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.
Authors: Ling-Yuan Kong; Adam S Wu; Tiffany Doucette; Jun Wei; Waldemar Priebe; Gregory N Fuller; Wei Qiao; Raymond Sawaya; Ganesh Rao; Amy B Heimberger Journal: Clin Cancer Res Date: 2010-10-04 Impact factor: 12.531
Authors: Shaik Ohidar Rahaman; Phyllis C Harbor; Olga Chernova; Gene H Barnett; Michael A Vogelbaum; S Jaharul Haque Journal: Oncogene Date: 2002-12-05 Impact factor: 9.867
Authors: Juliet V Spencer; Kristen M Lockridge; Peter A Barry; Gaofeng Lin; Monica Tsang; Mark E T Penfold; Thomas J Schall Journal: J Virol Date: 2002-02 Impact factor: 5.103
Authors: S Michelson; J Alcami; S J Kim; D Danielpour; F Bachelerie; L Picard; C Bessia; C Paya; J L Virelizier Journal: J Virol Date: 1994-09 Impact factor: 5.103
Authors: Daniel L Popkin; Mark A Watson; Elizabeth Karaskov; Gavin P Dunn; Rod Bremner; Herbert W Virgin Journal: Proc Natl Acad Sci U S A Date: 2003-11-12 Impact factor: 11.205
Authors: Charles S Cobbs; Lualhati Harkins; Minu Samanta; G Yancey Gillespie; Suman Bharara; Peter H King; L Burt Nabors; C Glenn Cobbs; William J Britt Journal: Cancer Res Date: 2002-06-15 Impact factor: 12.701
Authors: Alexia Ghazi; Aidin Ashoori; Patrick J Hanley; Vita S Brawley; Donald R Shaffer; Yvonne Kew; Suzanne Z Powell; Robert Grossman; Zakaria Grada; Michael E Scheurer; Meenakshi Hegde; Ann M Leen; Catherine M Bollard; Cliona M Rooney; Helen E Heslop; Stephen Gottschalk; Nabil Ahmed Journal: J Immunother Date: 2012 Feb-Mar Impact factor: 4.456
Authors: Kristine Dziurzynski; Susan M Chang; Amy B Heimberger; Robert F Kalejta; Stuart R McGregor Dallas; Martine Smit; Liliana Soroceanu; Charles S Cobbs Journal: Neuro Oncol Date: 2012-02-08 Impact factor: 12.300
Authors: Dimitrios Mathios; Jacob Ruzevick; Christopher M Jackson; Haiying Xu; Sagar R Shah; Janis M Taube; Peter C Burger; Edward F McCarthy; Alfredo Quinones-Hinojosa; Drew M Pardoll; Michael Lim Journal: J Neurooncol Date: 2014-10-28 Impact factor: 4.130
Authors: Joseph DiDomenico; Jonathan B Lamano; Daniel Oyon; Yuping Li; Dorina Veliceasa; Gurvinder Kaur; Leonel Ampie; Winward Choy; Jason B Lamano; Orin Bloch Journal: Oncoimmunology Date: 2018-04-25 Impact factor: 8.110
Authors: Smita K Nair; Gabriel De Leon; David Boczkowski; Robert Schmittling; Weihua Xie; Janet Staats; Rebecca Liu; Laura A Johnson; Kent Weinhold; Gary E Archer; John H Sampson; Duane A Mitchell Journal: Clin Cancer Res Date: 2014-03-21 Impact factor: 12.531
Authors: Orin Bloch; Courtney A Crane; Rajwant Kaur; Michael Safaee; Martin J Rutkowski; Andrew T Parsa Journal: Clin Cancer Res Date: 2013-04-23 Impact factor: 12.531