HCMV glycoprotein B is expressed in primary glioblastomas and enhances growth and invasiveness via PDGFR-alpha activation
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Charles Cobbs1,2,*, Sabeena Khan1,*, Lisa Matlaf1, Sean McAllister1, Alex Zider1, Garret Yount1, Kenneth Rahlin1, Lualhati Harkins3, Vladimir Bezrookove1, Eric Singer1, and Liliana Soroceanu1
1 California Pacific Medical Center Research Institute, San Francisco, CA
2 The Swedish Neuroscience Institute, Ben and Catherine Ivy Brain Tumor Center, Seattle, WA, and
3 University of Alabama at Birmingham, Birmingham AL
* These authors contributed equally to the work.
Liliana Soroceanu, email:
Keywords: Human Cytomegalovirus Glycoprotein B, glioblastoma, tumor invasiveness, Platelet Derived Growth Factor Receptor Alfa, slice invasion assay, time-lapse videomicroscopy.
Received: January 21, 2014 Accepted: March 10, 2014 Published: March 12, 2014
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.
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