Why do viruses cause cancer? Highlights of the first century of human tumour virology

Abstract

The year 2011 marks the centenary of Francis Peyton Rous's landmark experiments on an avian cancer virus. Since then, seven human viruses have been found to cause 10-15% of human cancers worldwide. Viruses have been central to modern cancer research and provide profound insights into both infectious and non-infectious cancer causes. This diverse group of viruses reveals unexpected connections between innate immunity, immune sensors and tumour suppressor signalling that control both viral infection and cancer. This Timeline article describes common features of human tumour viruses and discusses how new technologies can be used to identify infectious causes of cancer.

Timeline

Some major discoveries and events during the first century of tumour virology

Figure 1. Historical figures

a | The chicken tumour that started it all. This photograph from 1909 shows a sarcoma on the external chest wall of a chicken that was used by Francis Peyton Rous to discover the Rous sarcoma retrovirus. b | Vilhelm Ellerman (1871–1924), shown on the left, and his assistant, Oluf Bang (1881–1937), shown on the right. These Danish scientists first succeeded in transmitting a leukaemia-inducing avian retrovirus in 1908. These experiments formed a basis for Rous’s subsequent experiments showing a viral cause of a solid cancer. Images courtesy of Medical Museion, Copenhagen University, Denmark.

Figure 2. Common cellular targets for unrelated tumour virus oncoproteins

An incomplete but diverse list of animal and human tumour virus proteins that target RB1, p53, interferon and PI3K–mTOR signalling pathways. Most of these viral proteins are evolutionarily distinct from each other and have unique mechanisms for regulating or ablating these signalling pathways. Convergent evolution of tumour viruses to target these (and other cellular signalling pathways (not shown), including interleukin-6 (IL-6)–signal transducer and activator of transcription 3 signalling, telomerase and nuclear factor-κB (NF-κB) signalling pathways) reveals commonalities among the cancer viruses in tumour supressor and oncoprotein targeting. CBP, cAMP-response element binding protein; CDKI, cyclin-dependent kinase inhibitor; EBV, Epstein–Barr virus; HCV, hepatitis C virus; HPV, human papillomavirus; HTLV, human T-lymphotropic virus; IFNR, interferon receptor; IRF, interferon regulatory factor; KSHV, Kaposi’s sarcoma herpesvirus; LMP, latent membrane protein; miRNA, microRNA.

Figure 3. Two views for the origins of viral oncoproteins

a | The tumour virus proteins target RB1 and p53 to drive a quiescent G0 cell into S phase of the cell cycle, allowing viral access to the nucleotide pools and replication machinery that are needed for replication and transmission. Viral tumourigenesis is a by-product of the molecular parasitism by viruses to promote their own replication. Cells respond to virus infection by activating RB1 and p53 to inhibit virus replication as part of the innate immune response. To survive, tumour viruses have evolved the means for inactivating these and other immune signalling pathways that place the cell at risk for cancerous transformation. This view holds that many tumour suppressor proteins have dual functions in preventing cancer formation and virus infection. b | An illustration of the overlap between intracellular innate immune and tumour suppressor signalling. Under typical circumstances, viruses do not cause cancers except in the settings of immunosuppression and/or complementing host cell mutations. Non-tumorigenic viruses, which constitute the overwhelming majority of viruses, target many of the same innate immune and tumour suppressor pathways as tumour viruses but do so in ways that do not place the host at risk for carcinogenesis. Apart from p53, RB1 and p300, additional proteins are likely to have both tumour suppressor and innate immune functions.

Figure 4. The molecular evolution of a human tumour virus

Merkel cell polyomavirus (MCV), which has tumour-specific truncation mutations, illustrates common features among the human tumour viruses involving immunity, virus replication and tumour suppressor targeting. Although MCV is a common infection, loss of immune surveillance through ageing, AIDS or transplantation and subsequent treatment with immunosuppressive drugs may lead to resurgent MCV replication in skin cells. If a rare integration mutation into the host cell genome occurs, the MCV T antigen can activate independent DNA replication from the integrated viral origin that will cause DNA strand breaks in the proto-tumour cell. A second mutation that truncates the T antigen, eliminating its viral replication functions but sparing its RB1 tumour suppressor targeting domains, is required for the survival of the nascent Merkel tumour cell. Exposure to sunlight (possibly ultraviolet (UV) irradiation) and other environmental mutagens may enhance the sequential mutation events that turn this asymptomatic viral infection into a cancer virus.