Abstract
Human cytomegalovirus (HCMV) was first reported to be strongly associated with human malignant gliomas in 2002. HCMV is a herpesvirus that causes congenital brain infection and multi-organ disease in immumocompromised individuals. Malignant gliomas are the most common and aggressive adult brain tumors and glioblastoma multiforme (GBM), the highest grade glioma, is associated with a life expectancy of less than two years. HCMV gene products encode for multiple proteins that can promote the various signaling pathways critical to tumor growth, including those involved in mitogenesis, mutagenesis, apoptosis, inflammation, angiogenesis, invasion and immuno-evasion. Several groups have now demonstrated that human malignant gliomas are universally infected with HCMV and express gene products that can promote key signaling pathways in glioma pathogenesis. In this review I discuss specific HCMV gene products that we and others have recently found to be expressed in GBM in vivo, including the HCMV IE1, US28, gB and IL-10 proteins. The roles these HCMV gene products play in dysregulating key pathways in glioma biology, including the PDGFR, AKT, STAT3, and monocyte/microglia function are discussed. Finally, I review emerging human clinical trials for GBM based on anti-HCMV strategies.
Highlights
Human cytomegalovirus (HCMV) was first reported to be strongly associated with human malignant gliomas in 2002
Key signaling pathways involved in promoting glioblastoma multiforme (GBM) pathogenesis in the susceptible cell types. ie., neuoglial precursor stem cells (NPCs), are those that lead to sustained activation of receptor tyrosine kinase (RTK) signaling pathways such as EGFR and PDGFRa, and downstream PI3-K/AKT pathways, as well as those that inactivate important tumor suppressor pathways such as p16(INK4a), Rb, p53 and PTEN [3,11,12]
HCMV Ten years ago, our group became interested in the possibility that a viral infection might be involved in the pathogenesis of GBM since our research indicated that these tumors had characteristics of a chronic inflammatory state [21,22]
Summary
Human cytomegalovirus (HCMV) was first reported to be strongly associated with human malignant gliomas in 2002. Since TSP-1 inhibits angiogenesis and GFAP is associated with a more differentiated astrocytic phenotype [45], these results suggested that, in addition to promoting glioma cell mitogenesis, expression of IE1 in glioma cells may promote GBM angiogenesis, and a de-differentiated state, along with loss of tumor suppressor activity. While IE1 expression in a tumor cell may promote important oncogenic signaling pathways, we became interested in the possibility that HCMV might promote sustained RTK activation, which is a hallmark of GBM pathogenesis.
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