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  • Review Article
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Molecular mechanisms of viral oncogenesis in humans

Nature Reviews Microbiology volume 16, pages 684–698 (2018)Cite this article

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Abstract

Viral infection is a major contributor to the global cancer burden. Recent advances have revealed that seven known oncogenic viruses promote tumorigenesis through shared host cell targets and pathways. A comprehensive understanding of the principles of viral oncogenesis may enable the identification of unknown infectious aetiologies of cancer and the development of therapeutic or preventive strategies for virus-associated cancers. In this Review, we discuss the molecular mechanisms of viral oncogenesis in humans. We highlight recent advances in understanding how viral manipulation of host cellular signalling, DNA damage responses, immunity and microRNA targets promotes the initiation and development of cancer.

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Fig. 1: Signalling pathways targeted by oncogenic viruses.
Fig. 2: Viral oncoproteins and DNA damage responses influence the fate of the host cell.
Fig. 3: Modulation of host immune responses by oncogenic viruses.

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Acknowledgements

The authors thank E. A. White, C. B. Buck and the members of the You laboratory for valuable comments and suggestions on the manuscript. The authors apologize to all colleagues whose primary research papers could not be cited owing to space constraints. Research on human papilloma virus (HPV) and Merkel cell polyomavirus (MCPyV) in the You laboratory has been supported by National Institutes of Health (NIH) grants (R01CA187718, R01CA148768 and R01CA142723) and the National Cancer Institute (NCI) Cancer Center Support grant (NCI P30 CA016520).

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Nature Reviews Microbiology thanks D. Galloway and other anonymous reviewers for their contributions to the peer review of this work.

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  1. Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Nathan A. Krump & Jianxin You

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  1. Nathan A. Krump
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N.A.K. and J.Y. researched data for the article, substantially contributed to discussion of content, wrote the article and reviewed and edited the manuscript before submission.

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Correspondence to Jianxin You.

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Glossary terms

Oncogenic viruses

Viruses that cause cancer. Sometimes also called tumour viruses. However, some tumour viruses, such as adenovirus and polyomavirus SV40 promote tumorigenesis in other organisms and infect humans but do not cause human cancers.

Solid tumours

Masses of transformed and supporting cells that arise in stationary tissues (sarcomas and carcinomas) and not from cells of haematopoietic origin.

Lymphoma

Tumour arising from a lymphoid cell type that occurs predominantly in the lymphatics, as opposed to leukaemias, in which the cancer cells are found in the blood.

Cellular transformation

Selective acquisition of cellular traits, such as replicative immortality, increased stemness, growth factor independence, resistance to growth suppressors and alterations to metabolic flux.

Metastasis

Tumour migration, invasion and colonization of body sites other than the primary site.

p53

A transcription factor and key tumour suppressor downstream of exogenous signals and DNA damage-sensing pathways that maintains genome integrity and governs cell fate by promoting expression of effectors of DNA repair, cell cycle arrest, senescence and apoptosis.

pRB

(Retinoblastoma protein). A tumour suppressor that is responsible for a major G1 checkpoint that blocks S-phase entry and cellular growth.

Oncoproteins

Translated gene products that have the capacity to drive cellular transformation.

Kaposi sarcoma

A family of endothelial malignancies that are associated with Kaposi sarcoma-associated virus (KSHV) and whose members are classified by the type of immunosuppression that enabled KSHV-mediated oncogenesis.

Carcinomas

Tumours arising from cells of an epithelial origin, as opposed to sarcomas, which arise from mesenchymal cells.

Rapamycin

An inhibitor of mechanistic target of rapamycin (mTOR)-mediated proliferative function that acts through direct binding of the peptidyl-prolyl cis-trans isomerase FKBP1A–mechanistic target of rapamycin complex and has shown promise as an immunosuppressant and antitumour drug.

Sarcomagenesis

The seminal event or events leading to cancer progression from mesenchymal-derived cell types.

Cap-dependent translation

Translation in which initiation is mediated by recognition of the 5′ cap that is specific to eukaryotic mRNAs.

MEK1

(MAPK/ERK kinase 1 (also known as MAP2K1)). A crucial protein kinase that mediates an intermediate step of the RAF–MEK–ERK phosphorylation cascade responsible for activating expression of pro-proliferative, survival and differentiation genes in response to external stimuli.

Invasive cells

Tumour cells with characteristics that enable them to metastasize and invade other tissues.

Endothelial-to-mesenchymal transition

A process essential to cardiac development and normal angiogenesis by which endothelial cells acquire stem-like, mesenchymal traits including enhanced migration that, in certain cancers, contribute to metastatic ability.

Proto-oncogene

A type of endogenous gene that, when overexpressed or abnormally activated as a result of mutation, can promote cancer development, at which point it is referred to as an oncogene.

CHK2

(Checkpoint kinase 2). A tumour suppressor kinase activated by ataxia telangiectasia mutated (ATM) in response to double-stranded breaks in DNA that maintains genomic integrity by mediating cell cycle arrest and DNA repair.

Second messengers

Soluble small molecules that transduce intracellular signals, which can be secreted by intracellular bacteria to coordinate responses to their environment.

Inflammasome

A cytoplasmic complex of NOD-, LRR- and pyrin domain-containing proteins (NLRPs), adaptor proteins and caspases that forms in response to cellular damage or bacterial effectors that cause rapid caspase-mediated inflammatory cytokine release and/or a type of lytic cell death called pyroptosis.

T cell anergy

A process by which CD4+ or CD8+ T cells become tolerant to antigens and functionally inactivated owing to stimulation in the absence of a necessary signal.

CHK1

(Checkpoint kinase 1). A protein kinase essential to normal cell division and development that is activated by ataxia telangiectasia and Rad3-related protein (ATR) in response to single-stranded DNA to facilitate proper DNA replication, cell cycle progression and response to DNA insults.

Seed sequence

An eight-nucleotide sequence near the 5′-end of a microRNA that undergoes Watson–Crick base pairing with a target RNA with high specificity and that is required for efficient targeting.

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Krump, N.A., You, J. Molecular mechanisms of viral oncogenesis in humans. Nat Rev Microbiol 16, 684–698 (2018). https://doi.org/10.1038/s41579-018-0064-6

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