Glioblastoma multiforme (GBM), the most common and aggressive form of adult malignant brain cancer, kills 97% of patients within five years. No major advance in determining the etiology or improving therapy has occurred in 50 years. In 2002, we showed that human cytomegalovirus (HCMV) infection occurs in over 90% of GBMs. HCMV is the most common cause of congenital brain infection and encodes for gene products that dysregulate cell cycle, apoptosis, proliferation, immune response, angiogenesis, and cellular invasion. We demonstrated that expression of the essential HCMV IE1 gene can promote proliferation of primary GBM cells (Cobbs et. al. Can Res, 2008) and that activation of PDGFR1, a growth factor receptor implicated in gliomagenesis, is required for infection (Soroceanu et al., Nature, 2008). Our recent preliminary data indicate HCMV infection preferentially occurs in the CD133+ stem-like pool of GBM cells in vivo, and induces genes that sustain the cancer stem cell phenotype. Based on this evidence, we hypothesize HCMV plays a role in initiation and promotion of GBM pathogenesis. We will focus on three essential questions to test our hypothesis: 1) Which HCMV genes are expressed in vivo in GBM and do they promote glioma pathogenesis?, 2) Does HCMV infection induce tumor formation or promote the glioma phenotype in uninfected cells of glial lineage?, and 3) Do "oncogenic" HCMV strains occur in vivo in GBM cells? We will utilize our tumor tissue bank, our extensive in vitro and in vivo brain tumor expertise, and the expertise of collaborators at OHSU and UAB for viral gene array and viral characterization experiments to answer these questions. If we demonstrate that HCMV infection plays a role in the etiology and/or progression of malignant glioma, this paradigm shift in our understanding of this disease will lead to novel therapeutic or even preventive agents for GBM.

Public Health Relevance

Malignant gliomas, which have no known cause, are the most common primary brain tumors, are diagnosed in about 20,000 Americans per year, and are almost 100% fatal within five years. We have discovered that a common human virus, cytomegalovirus (CMV), is found specifically in almost 100% of these tumors and we hypothesize that CMV may cause and / or promote growth of these tumors by expressing genes that drive malignancy. We have planned several experiments that will allow us to determine whether CMV plays a role of CMV in malignant glioma biology - a finding that would have a major impact on our understanding of this cancer and lead to radically new therapies and prevention strategies based on antiviral approaches.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
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Fountain, Jane W
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Swedish Medical Center, First Hill
United States
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Cobbs, Charles; Khan, Sabeena; Matlaf, Lisa et al. (2014) HCMV glycoprotein B is expressed in primary glioblastomas and enhances growth and invasiveness via PDGFR-alpha activation. Oncotarget 5:1091-100
Ulasov, Ilya; Yi, Ruiyang; Guo, Donna et al. (2014) The emerging role of MMP14 in brain tumorigenesis and future therapeutics. Biochim Biophys Acta 1846:113-20
Matlaf, Lisa A; Harkins, Lualhati E; Bezrookove, Vladimir et al. (2013) Cytomegalovirus pp71 protein is expressed in human glioblastoma and promotes pro-angiogenic signaling by activation of stem cell factor. PLoS One 8:e68176
Cobbs, Charles S (2013) Cytomegalovirus and brain tumor: epidemiology, biology and therapeutic aspects. Curr Opin Oncol 25:682-8
Hadaczek, Piotr; Ozawa, Tomoko; Soroceanu, Liliana et al. (2013) Cidofovir: a novel antitumor agent for glioblastoma. Clin Cancer Res 19:6473-83
Soroceanu, Liliana; Matlaf, Lisa; Bezrookove, Vladimir et al. (2011) Human cytomegalovirus US28 found in glioblastoma promotes an invasive and angiogenic phenotype. Cancer Res 71:6643-53
Cobbs, Charles S (2011) Evolving evidence implicates cytomegalovirus as a promoter of malignant glioma pathogenesis. Herpesviridae 2:10