Glioblastoma (GBM) is the most common primary brain tumor in adults and is uniformly fatal. Our laboratory was the first to show that human cytomegalovirus (HCMV) nucleic acids and proteins are present in over 90% of human malignant gliomas, and these findings have now been confirmed by three independent groups. Recent studies have shown that HCMV infection levels negatively correlate with patient survival, suggesting that HCMV may induce a shift towards a more aggressive and invasive glioma phenotype. We recently published two reports demonstrating that HCMV infection and gene expression in GBM cells can induce cellular tyrosine kinase signaling pathways critical for tumor growth (Akt, PLC3, FAK), inhibit p53 and Rb tumor suppressor activity, alter cell cycle checkpoint controls, and promote cell proliferation. We have also discovered that HCMV activates robust PDGFR1 signaling in GBM cells, and that PDGFR1 activation is actually required for HCMV infection. This finding is particularly relevant to glioma biology since PDGFR1 is amplified/overexpressed in a high percentage of GBM cells and activation of PDGFR1 in normal NPCs is implicated in the earliest stages of gliomagenesis. Our published and preliminary data indicate that HCMV glycoprotein B (gB, the most abundant viral envelope protein) is the viral moiety that binds and Tyrosine phosphorylates PDGFR1 and activates downstream PI3K-Akt signaling in glioma cells. Most recently, we have evidence that gB induces haptotactic glioma cell migration and that HCMV-induced glioma transwell migration is inhibited both by PDGFR1 blocking antibodies or gB neutralizing antibodies. Taken together, our data suggest that the interaction between HCMV gB and PDGFR1 expressed on the surface of glioma cells may play a critical role in modulating glioma growth and invasion. To investigate these hypotheses, we propose to use in vitro, ex vivo, and in vivo assays which will test whether HCMV-infected and gB -expressing human glioma cells exhibit enhanced growth and invasiveness. Our laboratory has unique access to human primary glioblastoma-derived cultures which endogenously express several HCMV gene products, including gB. We plan to use these primary glioma cultures, super-infected with a clinical HCMV isolate and engineered to ectopically express gB for transwell migration, brain slice invasion, and in vivo tumor growth assays. If we find that HCMV and gB do promote glioma growth and invasiveness, we plan to investigate specific mechanisms underlying this modulation, including cell proliferation, cell invasion, and tumor angiogenesis. Results from these experiments will be critical in understanding the role that HCMV plays in the pathogenesis of human gliomas and may uncover novel therapeutic approaches against this incurable human cancer, based on antiviral strategies.
Our laboratory has found that a common human virus, cytomegalovirus (HCMV) is present in over 90% of malignant gliomas, a uniformly fatal, highly aggressive cancer, with no known etiology or treatment. This proposal will investigate the role of HCMV envelope glycoprotein B in promoting glioma growth and invasion. Results from experiments proposed herein may lead to novel therapeutic approaches based on antiviral treatments for glioma patients.
