title: HCMV glycoprotein B is expressed in primary glioblastomas and enhances growth and invasiveness via PDGFR-alpha activation.
abstract: Our laboratory first demonstrated that human cytomegalovirus (HCMV) is associated with the most deadly form of primary brain tumor, glioblastoma (GBM). We showed that HCMV glycoprotein B (gB) mediates viral cellular entry via the receptor tyrosine kinase PDGFR-alpha (PDGFRα), resulting in activation of the PI3K/Akt pathway, a critical signaling axis gliomagenesis. Here, we investigated the effects of gB overexpression on glioma progression. We demonstrate that gB is endogenously expressed in primary GBM samples and show that ectopic gB expression in glioma cells induced sustained phosphorylation of PDGFRα, Akt, and Src. Recombinant gB protein and the whole virus enhanced invasion of primary glioblastoma cells into Matrigel and rat brain slices, and this effect was specifically inhibited by neutralizing antibodies to either gB or PDGFRα. Importantly, neutralizing antibodies to gB significantly inhibited the invasiveness of patient-derived HCMV-positive glioblastoma cells, suggesting that functional inhibition of this viral protein could hinder glioblastoma progression. gB overexpression promoted in vivo glioma growth and enhanced phosphor-Akt levels and tumor cell dispersal relative to controls. Taken together, our results demonstrate that HCMV gB promotes key hallmarks of glioblastoma and suggest that targeting gB may have therapeutic benefits for patients with HCMV-positive gliomas.
authors.affiliation: California Pacific Medical Center Research Institute, San Francisco, CA.
authors.forename: Charles
authors.initials: C
authors.lastname: Cobbs
authors.forename: Sabeena
authors.initials: S
authors.lastname: Khan
authors.forename: Lisa
authors.initials: L
authors.lastname: Matlaf
authors.forename: Sean
authors.initials: S
authors.lastname: McAllister
authors.forename: Alex
authors.initials: A
authors.lastname: Zider
authors.forename: Garret
authors.initials: G
authors.lastname: Yount
authors.forename: Kenneth
authors.initials: K
authors.lastname: Rahlin
authors.forename: Lualhati
authors.initials: L
authors.lastname: Harkins
authors.forename: Vladimir
authors.initials: V
authors.lastname: Bezrookove
authors.forename: Eric
authors.initials: E
authors.lastname: Singer
authors.forename: Liliana
authors.initials: L
authors.lastname: Soroceanu
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D003587:Cytomegalovirus / Q000378:metabolism*; D003586:Cytomegalovirus Infections / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D005260:Female; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D064593:Heterografts; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D051381:Rats; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism*; D015398:Signal Transduction; D014759:Viral Envelope Proteins / Q000096:biosynthesis*
chemical_list: D014759:Viral Envelope Proteins; C040495:glycoprotein B, Simplexvirus; D020796:Receptor, Platelet-Derived Growth Factor alpha