Abstract
Like all other mammals, humans harbour an astonishing number of endogenous retroviruses (ERVs), as well as other retroelements, embedded in their genome. These remnants of ancestral germline infection with distinct exogenous retroviruses display various degrees of open reading frame integrity and replication capability. Modern day exogenous retroviruses, as well as the infectious predecessors of ERVs, are demonstrably oncogenic. Further, replication-competent ERVs continue to cause cancers in many other species of mammal. Moreover, human cancers are characterized by transcriptional activation of human endogenous retroviruses (HERVs). These observations conspire to incriminate HERVs as causative agents of human cancer. However, exhaustive investigation of cancer genomes suggests that HERVs have entirely lost the ability for re-infection and thus the potential for insertional mutagenic activity. Although there may be non-insertional mechanisms by which HERVs contribute to cancer development, recent evidence also uncovers potent anti-tumour activities exerted by HERV replication intermediates or protein products. On balance, it appears that HERVs, despite their oncogenic past, now represent potential targets for immune-mediated anti-tumour mechanisms.This article is part of the themed issue ‘Human oncogenic viruses’.
Highlights
Our increasing understanding of the aetiology of cancer has implicated viral infection as the direct cause of as many as one in five human cancers [1]
Serum titres of human endogenous retroviruses (HERVs)-K-reactive antibodies correlate positively with disease activity in humans, both in patients with germ cell tumours [112] and in those with melanoma [108]. These findings suggest that humoral responses against HERV-K antigens might either reflect or even contribute to disease severity, a link that will need to be further investigated
Endogenous retroelements have been intricately linked to the development of cancer
Summary
Our increasing understanding of the aetiology of cancer has implicated viral infection as the direct cause of as many as one in five human cancers [1]. The concept of a cancer-causing virus dates back to the landmark discovery of Rous sarcoma virus (RSV), an infectious oncogenic retrovirus inducing sarcomas in domestic fowl [2] It was the study of transmissible animal retroviruses such as RSV and avian leukosis virus in domestic fowl, as well as murine leukaemia virus and mouse mammary tumour virus in laboratory mice that established the first principles in cancer research [3] and forged a strong link between retroviruses and cancer in the mindset of the research community [4]. The study of the same animal retroviruses and the cancers they were causing in animals eventually led to the discovery of endogenous retroviruses (ERVs) [5,6,7], reinforcing the link between retroviruses and cancer This putative link developed almost into an obsession in the research community, who began hunting for retroviruses, exogenous as well as endogenous, as causative agents of many different types of cancer and other human conditions [8]. Based on the accumulating evidence, we would suggest that these once infectious and potentially oncogenic agents have been conscripted to help protect the host
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