title: Cytomegalovirus contributes to glioblastoma in the context of tumor suppressor mutations.
abstract: To study the controversial role of cytomegalovirus (CMV) in glioblastoma, we assessed the effects of murine CMV (MCMV) perinatal infection in a GFAP-cre; Nf1(loxP/+); Trp53(-/+) genetic mouse model of glioma (Mut3 mice). Early on after infection, MCMV antigen was predominantly localized in CD45+ lymphocytes in the brain with active viral replication and local areas of inflammation, but, by 7 weeks, there was a generalized loss of MCMV in brain, confirmed by bioluminescent imaging. MCMV-infected Mut3 mice exhibited a shorter survival time from their gliomas than control Mut3 mice perinatally infected with mock or with a different neurotropic virus. Animal survival was also significantly shortened when orthotopic gliomas were implanted in mice perinatally infected with MCMV versus controls. MCMV infection increased phosphorylated STAT3 (p-STAT3) levels in neural stem cells (NSC) harvested from Mut3 mice subventricular zone, and, in vivo, there was increased p-STAT3 in NSCs in MCMV-infected compared with control mice. Of relevance, human CMV (HCMV) also increased p-STAT3 and proliferation of patient-derived glioblastoma neurospheres, whereas a STAT3 inhibitor reversed this effect in vitro and in vivo. These findings thus associate CMV infection to a STAT3-dependent modulatory role in glioma formation/progression in the context of tumor suppressor mutations in mice and possibly in humans.
authors.affiliation: Department of Neurological Surgery, Dardinger Neuro-oncology Center, Solid Tumor Program at the James Comprehensive Cancer Center, Center for Biostatistics, Departments of Pathology, Veterinary Biosciences, and Surgery, The Ohio State University Medical Center, Columbus, Ohio, USA.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Price
authors.forename: Jieun
authors.initials: J
authors.lastname: Song
authors.forename: Katherine
authors.initials: K
authors.lastname: Bingmer
authors.forename: Tae Hyong
authors.initials: TH
authors.lastname: Kim
authors.forename: Ji-Yeun
authors.initials: JY
authors.lastname: Yi
authors.forename: Michal O
authors.initials: MO
authors.lastname: Nowicki
authors.forename: Xiaokui
authors.initials: X
authors.lastname: Mo
authors.forename: Todd
authors.initials: T
authors.lastname: Hollon
authors.forename: Eric
authors.initials: E
authors.lastname: Murnan
authors.forename: Christopher
authors.initials: C
authors.lastname: Alvarez-Breckenridge
authors.forename: Soledad
authors.initials: S
authors.lastname: Fernandez
authors.forename: Balveen
authors.initials: B
authors.lastname: Kaur
authors.forename: Andreana
authors.initials: A
authors.lastname: Rivera
authors.forename: Michael
authors.initials: M
authors.lastname: Oglesbee
authors.forename: Charles
authors.initials: C
authors.lastname: Cook
authors.forename: E Antonio
authors.initials: EA
authors.lastname: Chiocca
authors.forename: Chang-Hyuk
authors.initials: CH
authors.lastname: Kwon
mesh_terms: D000818:Animals; D001927:Brain Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000821:virology; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D003587:Cytomegalovirus / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D003586:Cytomegalovirus Infections / Q000235:genetics / Q000473:pathology* / Q000821:virology; D005260:Female; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D064593:Heterografts; D006801:Humans; D008297:Male; D051379:Mice; D041681:NIH 3T3 Cells; D011247:Pregnancy; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D013489:Suppression, Genetic; D014779:Virus Replication
chemical_list: D050796:STAT3 Transcription Factor