Tumor viruses and cancer biology: Modulating signaling pathways for therapeutic intervention

Abstract

Tumor viruses have provided relatively simple genetic systems, which can be manipulated for understanding the molecular mechanisms of the cellular transformation process. A growing body of information in the tumor virology field provides several prospects for rationally targeted therapies. However, further research is needed to better understand the multiple mechanisms utilized by these viruses in cancer progression in order to develop therapeutic strategies. Initially viruses were believed to be associated with cancers as causative agents only in animals. It was almost half a century before the first human tumor virus, Epstein-Barr virus (EBV), was identified in 1964. Subsequently, several human tumor viruses have been identified including Kaposi sarcoma associated herpesvirus (KSHV), human Papillomaviruses (HPV), Hepatitis B virus (HBV), Hepatitis C virus (HCV), Human T lymphotropic virus (HTLV-1) and recently identified Merkel cell Polyomavirus (MCPyV). Tumor viruses are sub-categorized as either DNA viruses, which include EBV, KSHV, HPV, HBV, and MCPyV, or RNA viruses such as HCV and HTLV-1. Tumor-viruses induce oncogenesis through manipulating an array of different cellular pathways. These viruses initiate a series of cellular events, which lead to immortalization and proliferation of the infected cells by disrupting the mitotic checkpoint upon infection of the host cell. This is often accomplished by functional inhibition or proteasomal degradation of many tumor suppressor proteins by virally encoded gene products. The virally infected cells can either be eliminated via cell-mediated apoptosis or persist in a state of chronic infection. Importantly, the chronic persistence of infection by tumor viruses can lead to oncogenesis. This review discusses the major human tumor associated viruses and their ability to modulate numerous cell signaling pathways, which can be targeted for potential therapeutic approaches.

Figure 1

Tumor virus infection leads to immortalization of the infected cell through deregulation of cellular homeostasis. Via expression of many potent oncoproteins tumor virus promote an aberrant cell-proliferation via modulating cellular cell-signaling pathways and escape from cellular defense system such as blocking apoptosis. Subsequently primary cancerous cells become metastatic through inhibiting cellular metastasis suppressor proteins.

Figure 2

Tumor virus encoded oncoproteins deregulate components of the cell cycle and apoptotic pathways. Viral-oncoproteins (red) interact with and manipulate normal functions of numerous cellular important proteins (black) to hijack entire cell cycle and apoptotic machineries.

Figure 3

Epigenetic regulation by tumor virus encoded oncoproteins. Schematic showing epigenetic control of gene transcription by alterations in DNA methylation status and chromatin modifications by tumor virus encoded oncoproteins (red). Transcriptionally active DNA represents an open chromatin structure with widely spaced nucleosomes, associated with unmethylated CpG residues and specific post translational histone modifications, including increased levels of acetylation as well as other enzymes and co-factors. On the other hand, transcriptionally repressive conformation of DNA is characterized by methylated CpG islands, compacted nucleosomes, with deacetylated histones, and further post translational modifications, including methylation of specific histone H3 lysine residues. This repressive conformation renders the DNA inaccessible to the transcriptional machinery. MBPs, methyl-CpG binding proteins; HDACs, histone deacetylases; DNMTs, DNA methyltransferases; HATs, histone acetyl transferase.

Figure 4

Tumor virus encoded oncoproteins hijack major cell-signaling pathways. Viral-oncoproteins (red) interact with and control major cellular signaling pathways which ultimately lead to immortalization and continuous proliferation of the virus infected cells.