Viral Oncology: Molecular Biology and Pathogenesis

Abstract

Oncoviruses are implicated in approximately 12% of all human cancers. A large number of the world's population harbors at least one of these oncoviruses, but only a small proportion of these individuals go on to develop cancer. The interplay between host and viral factors is a complex process that works together to create a microenvironment conducive to oncogenesis. In this review, the molecular biology and oncogenic pathways of established human oncoviruses will be discussed. Currently, there are seven recognized human oncoviruses, which include Epstein-Barr Virus (EBV), Human Papillomavirus (HPV), Hepatitis B and C viruses (HBV and HCV), Human T-cell lymphotropic virus-1 (HTLV-1), Human Herpesvirus-8 (HHV-8), and Merkel Cell Polyomavirus (MCPyV). Available and emerging therapies for these oncoviruses will be mentioned.

Keywords: EBV; HBV; HCV; HHV-8; HPV; HTLV-1; MCPyV; human oncovirus; viral oncology.

Figure 1

Major patterns of Epstein-Barr virus (EBV) latent gene expression in lymphoproliferative disorders. The main EBV latency patterns and the most common lymphoproliferative disorders in which these patterns are seen are illustrated. Reproduced with permission from Cesarman, E., Gammaherpesvirus and lymphoprolliferative disorders in immunocompromised patients; published by Cancer Lett., 2011.

Figure 2

Diagrammatic representation of the cellular signaling pathways in maintaining latency. HHV-8 genome persists as a latent episome within the infected cells by expressing a limited number of viral genes during latency. For a successful establishment of latency, Human Herpesvirus-8 (HHV-8) manipulates and deregulates multiple viral and cellular signaling pathways. HHV-8 latent genes, including latency-associated nuclear antigen-1 (LANA), viral FLICE inhibitory protein (v-FLIP), microRNAs (miRNA), and viral Cyclin (v-Cyclin) activate and maintain various cytokine-mediated cell proliferation and tumorigenesis pathways, such as mitogen-activated protein kinase (MAPK), Janus kinase/signal transducer and activator of transcription (JAK/STAT), mitogen-activated protein kinase/extracellular-signal regulated kinase (MEK/ERK), phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR), Notch, Wingless-related integration site (Wnt), cMyc, p53, retinoblastoma (RB), and nuclear factor-κB (NF-κB), to maintain latent infection. Reproduced with permission from Purushothaman, P., KSHV Genome Replication and Maintenance; published by Front. Microbial., 2016.

Figure 3

Merkel Cell Polyomavirus (MCPyV) genome organization. Non-coding control region (NCCR): bipartite origin of replication. Early gene region: Large T antigen (LT), small T antigen (ST), 57kT antigen (57kT), alternative T antigen open reading frame (ALTO), microRNA (miRNA). Late gene region: capsid proteins (VP1-3). Reproduced with permission from Stakaitytė, G., Merkel Cell Polyomavirus: Molecular Insights into the Most Recently Discovered Human Tumour Virus; published by Cancers, 2014.

Figure 4

Models of MCPyV-induced Merkel cell carcinoma (MCC) tumourigenesis. MCPyV infection is thought to occur early in childhood of most people. Before tumourigenesis can occur, loss immunosurveillance must lead to proliferation of the virus. At least two mutations are needed before MCPyV can transform cells. In model A, the first mutation is thought to be the integration of the full-length viral genome into host DNA, while the second mutation is the truncation of LT. In model B, truncation of LT is thought to occur before integration. Either way, these changes in the virus lead to cellular transformation and tumour proliferation. Reproduced with permission from Stakaitytė, G., Merkel Cell Polyomavirus: Molecular Insights into the Most Recently Discovered Human Tumour Virus; published by Cancers, 2014.

Figure 5

Role of Inflammation in Tumor Initiation and Promotion. (A) Tumor initiation. Reactive oxygen species (ROS) and reactive nitrogen intermediates (RNI) produced by inflammatory cells may cause mutations in neighboring epithelial cells. Also, cytokines produced by inflammatory cells can elevate intracellular ROS and RNI in premalignant cells. In addition, inflammation can result in epigenetic changes that favor tumor initiation. Tumor associated inflammation contributes to further ROS, RNI, and cytokine production; (B) Tumor promotion. Cytokines produced by tumor-infiltrating immune cells activate key transcription factors, such as NF-κB or STAT3, in premalignant cells to control numerous protumorigenic processes, including survival, proliferation, growth, angiogenesis, and invasion. As parts of positive feed-forward loops, NF-κB and STAT3 induce production of chemokines that attract additional immune/inflammatory cells to sustain tumor-associated inflammation. Reproduced with permission from Grivennikov, S.I., Immunity, Inflammation, and Cancer; published by Cell, 2010.

Figure 6

Hepatitis C virus (HCV)-related mechanisms of carcinogenesis: from HCV infection to hepatocellular carcinoma (HCC). Chronic HCV and associated liver cirrhosis represent major risk factors for HCC development. Hepatocarcinogenesis is a multistep process that may last for years; it involves progressive accumulation of different genetic alterations which lead to malignant transformation. Malignant transformation of hepatocytes occurs through increased liver cell turnover, induced by chronic liver injury and regeneration, in the context of inflammation and oxidative stress. HCV proteins may directly upregulate mitogenic pathways, block cell death and induce reactive oxygen species (ROS) production. Moreover, HCV triggers persistent inflammation with accumulation of liver-infiltrating lymphocytes and production of several cytokines, such as LTα and LTβ, which are tightly linked to HCC development. Chronic inflammation exacerbates ROS production, which is considered a main source of genetic mutations. ROS are also associated with TGF-β pathway induction, leading to hepatic stellate cell activation and fibrogenesis. Transforming growth factor-β (TGF-β), together with TLR4, plays an important role in the epithelial–mesenchymal transition. HCV dysregulates host lipid metabolism, causing liver fat accumulation which in many patients is associated with HCC. HCV is also able to induce angiogenic and metastatic pathways. Polymorphisms, mainly in DEPDC5 and MICA genes, have been recently shown to increase the risk of developing HCC. HCC, hepatocellular carcinoma; HCV, hepatitis C virus; ROS, reactive oxygen species; TGF, transforming growth factor. Reproduced with permission from Vescovo, T., Molecular mechanisms of hepatitis C virus–induced hepatocellular carcinoma; published by Clin. Microbiol. Infect., 2016.

Figure 7

Examples of cutaneous lesions observed in ATL. (A) Chronic form with papular pattern; (B) Acute form showing exfoliative erythroderma; (C) Smoldering form with a pattern of papules and erythematous scaly plaques; (D) Primary cutaneous tumoral form. Reproduced with permission from Oliveira P.D., Adult T-cell leukemia/lymphoma; published by Rev. Assoc. Med. Bras., 2016.

Figure 8

Recommended treatment strategy for patients with acute, lymphoma or chronic and smoldering subtypes of adult T-cell leukemia/lymphoma (ATL). CR: complete remission, MRD: minimal residual disease, AZT: zidovudine, IFN: interferon alpha, alloSCT: allogeneic stem cell transplantation, HDAC: histone deacetylase. Reproduced with permission from Marçais, A., Therapeutic options for adult T-Cell leukemia/lymphoma; published by Curr. Oncol. Rep., 2013.