Review
Oncomodulatory mechanisms of human cytomegalovirus in gliomas

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Abstract

Human cytomegalovirus (HCMV), a widespread beta-herpes virus, infects a high percentage of high grade gliomas. Although HCMV is not recognized as an oncogenic virus, it might increase the malignancy of the infected cell by disrupting cellular pathways involved in the cell cycle, apoptosis, angiogenesis, cell invasion and the host immune response. This article reviews the recent evidence of the modulatory effects of HCMV infection leading to the malignant progression of gliomas and explores novel therapeutic targets against such lethal tumors.

Introduction

HCMV infections are the leading cause of viral-induced birth defects, affecting the central nervous system primarily.1 Serious neurologic deficits associated with the congenital and neonatal infection include seizures, deafness, blindness, mental retardation, hydrocephalus and microcephaly.2 HCMV also infects between 50% and 80% of adults in the USA and can be life-threatening in immunocompromised patients.3 Most healthy people infected by HCMV after birth are asymptomatic yet become life-long latent carriers.4

The neuropathology of HCVM infection remains poorly understood. Neural progenitor cells and astrocytes are permissive cell types for infection.[5], [6] Moreover, the state of differentiation bears significance to the permissiveness of the virus.5 The HCMV genome encodes more than 200 proteins, and their expression occurs in a program of three sequential stages: immediate–early (IE) proteins are synthesized, which activate early genes necessary for replication; early (E) proteins; and late (L) proteins, which represent structural components of the virus.7 The infected permissive cells generally produce large quantities of the virus.8

The presence of HCMV antigens, as well as the intact virus itself, has been reported in various malignancies including malignant gliomas, colorectal cancers, prostate cancer and cutaneous malignancies.[9], [10], [11], [12] In 2002, Cobbs et al. were the first group to report the association between HCMV and malignant gliomas.9 They observed that HCMV nucleic acids and proteins were present in a high percentage of high-grade and low-grade gliomas (World Health Organization [WHO] grades II–IV) and that the expression of early and delayed gene products occurred in these tumors.9 The HCMV immediate–early-1 (IE-1) protein was detected in >90% of gliomas. Nearly 80% of newly diagnosed patients with glioblastoma multiforme (GBM) have HCMV DNA in their peripheral blood suggesting either systemic reactivation or viral shedding from tumor cells to the periphery.13 Moreover, patients with GBM who have a low viral load live twice as long compared to patients with high levels of infection.[4], [14] Scheurer et al. have shown immunoreactivity against the HCMV IE-1 antigen, which exhibits a histology-specific pattern with more nuclear staining for anaplastic and low-grade gliomas, while GBM show nuclear and cytoplasmic staining suggestive of latent infection.15

The exact role of HCMV in these cancers is under investigation. There is no conclusive evidence of the transformation of normal human cells after HCMV infection. The term “oncomodulation” was coined to infer that the virus may modulate the malignant properties of the tumor cells through mechanisms that affect the cell cycle, survival, invasive potential, chromosomal stability, immunodetection and angiogenic properties.16 Oncomodulation implies that HCMV infects established tumor cells and increases their malignant potential without necessarily being oncogenic. According to this hypothesis, glioma cells provide a genetic environment, characterized by disturbances in intracellular signaling pathways, transcriptional control and tumor suppressor proteins, that enables HCMV to exert its oncomodulatory potential in tumor cells but not in normal cells. Table 1 summarizes these findings.

Section snippets

Effects of HCMV on the glioma cell cycle

Gliomas are the most common form of primary brain tumor in adults and, due to their infiltrative and invasive nature, remain clinically intractable despite aggressive treatment. Median survival after standard therapy including surgical resection, chemotherapy and radiation is only 14 months.17 Gliomas are of glial cell origin. A growing number of publications suggests that these tumors originate from stem cells.18 Singh et al. have isolated a cell type from gliomas that might represent the

Effects of HCMV on cell migration and invasion

An important hallmark of malignant gliomas is their invasive behavior. This property is linked to cell–extracellular matrix interaction involving integrins, focal adhesion kinase (FAK) and PI3K signaling.41 FAK is a non-receptor tyrosine kinase involved in the regulation of cell cycle progression, cell survival and cell migration. It is activated by integrin-mediated adhesion to the extracellular matrix (ECM) as well as by growth factor stimulation.41 FAK promotes cell migration in vitro and in

Effects of HCMV on angiogenesis

The development of new blood vessels (angiogenesis) is necessary to sustain the growth, invasion, and metastasis of tumors. Angiogenesis is a crucial step in the malignant progression of gliomas and microvascular proliferation is a histopathological hallmark of GBM.[48], [49] Tumor angiogenesis involves a complex interplay of pro-angiogenic and anti-angiogenic factors that include endothelial cell proliferation, migration, and reorganization of the extracellular matrix.[48], [49] Vascular

Effects of HCMV on the immune system

The cytokine transforming growth factor beta (TGF-β) has been recognized as the most prominent glioblastoma-associated immunosuppressant.57 It is a multifunctional cytokine that not only interferes with multiple steps of the immune response, but also induces migration, invasion, and angiogenesis. Inhibitory effects on T, B, natural killer (NK) cells, macrophages, microglial and dendritic cells are well recognized.57 TGF-β negatively regulates major histocompatibility complex (MHC) class II

Therapeutic implications

Various groups are now focusing on HCMV as a therapeutic target for patients with glioblastoma. Prins et al. have demonstrated a CMV-specific CD8+ T-cell response induced in a patient with glioblastoma after therapeutic vaccination with dendritic cells pulsed with an autologous tumor lysate, which suggests that HCMV in gliomas could serve as an immunotherapeutic target.62

Mitchell et al. (as discussed in Miller63) have vaccinated patients with glioblastoma with immune cells exposed to CMV

Summary

This review summarizes the oncomodulatory effects of HCMV in gliomas and their relevance in their pathogenesis, and thus serves as a resource for future efforts to develop novel treatment strategies against such deadly tumors.

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