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.
Highlights
Human primary brain tumors, including the most common and malignant type- glioblastoma (GBM) are extremely lethal cancers, with a median patient survival of~14 months
Confocal microscopy of glioma cells revealed that to PDGF-AA, human cytomegalovirus (HCMV) induced stress fiber reorganization as demonstrated by vinculin and β3 integrin co-localization and this process was dependent on PDGFRα and Src activation, since it was blocked by pretreatment with 3G3 (10 μg/ml) or PP1 (2.5mM, Figure 1C)
Several laboratories have shown that HCMV and HCMV glycoprotein B is found in a majority of human primary glioblastomas
Summary
Human primary brain tumors (gliomas), including the most common and malignant type- glioblastoma (GBM) are extremely lethal cancers, with a median patient survival of~14 months. Malignant gliomas are highly invasive tumors, infiltrating the surrounding healthy brain tissue, which makes complete tumor removal by surgery unlikely. Our laboratory first reported that human cytomegalovirus (HCMV) gene products are expressed in over 90% of GBMs, while absent in the surrounding non-malignant brain tissue. These findings have been confirmed by several other groups [1,2,3] To date, the role of HCMV proteins in the pathogenesis of malignant gliomas has not been elucidated. We recently discovered that activation of a receptor tyrosine kinase implicated in the pathology of gliomas, human platelet-derived growth factor alpha receptor (PDGFRα) is required for HCMV infection[4]. We further determined that HCMV glycoprotein B (gB, the most abundant viral envelope glycoprotein) is the viral moiety that directly interacts with and tyrosine phosphorylates www.impactjournals.com/oncotarget
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