Viral Causality of Human Cancer and Potential Roles of Human Endogenous Retroviruses in the Multi-Omics Era: An Evolutionary Epidemiology Review

Abstract

Being responsible for almost 12% of cancers worldwide, viruses are among the oldest known and most prevalent oncogenic agents. The quality of the evidence for the in vivo tumorigenic potential of microorganisms varies, thus accordingly, viruses were classified in 4 evidence-based categories by the International Agency for Research on Cancer in 2009. Since then, our understanding of the role of viruses in cancer has significantly improved, firstly due to the emergence of high throughput sequencing technologies that allowed the "brute-force" recovery of unknown viral genomes. At the same time, multi-omics approaches unravelled novel virus-host interactions in stem-cell biology. We now know that viral elements, either exogenous or endogenous, have multiple sometimes conflicting roles in human pathophysiology and the development of cancer. Here we integrate emerging evidence on viral causality in human cancer from basic mechanisms to clinical studies. We analyze viral tumorigenesis under the scope of deep-in-time human-virus evolutionary relationships and critically comment on the evidence through the eyes of clinical epidemiology, firstly by reviewing recognized oncoviruses and their mechanisms of inducing tumorigenesis, and then by examining the potential role of integrated viruses in our genome in the process of carcinogenesis.

Keywords: Viruses in Human Tumorigenesis; cancer; endogenous retroviruses; evolutionary epidemiology; viral tumorigenesis; viruses.

Figure 1

Mechanisms involved in the EBV-associated carcinogenesis: CircBARTs and circRPMS1 are implicated in the cellular immortalization and the induction of uncontrolled proliferation. CircRPMS1 is negatively correlated to the expression of innate oncosuppressor miRNAs (miR-31, miR-230 and miR-541), as observed in NPC. Gene expression modification takes place in B-cell malignancies, as a result of the methylation pattern-modifications caused by the EBV infection through the EBV LMP1 mediated upregulation of DNMT-3A and the downregulation of DNMT-1 and DNMT-3B (EBV, Epstein–Barr Virus; circBARTs, circular BamHI A rightward transcripts; miRNAs, microRNAs; NPC, Nasopharyngeal Carcinoma; EBV LMP1, EBV latent membrane protein 1; DNMT, DNA methyltranserase). Created in BioRender.com.

Figure 2

Oncogenic mechanisms in the development of MCPyV-related MCC: Indirect binding of p53 and inhibition of Rb proteins due to LT and tLT antigens of MCPyV lead to cellular immortalization and malignant transformation. LT and sT antigens contribute to the evasion of the immune system mechanisms by downregulating MHC-I and TLR-9. Viral DNA integration to the host genome participates in genome instability. (MCPyV, Merkel Cell Polyomavirus; MCC, Merkel Cell Carcinoma; LT, Large T; tLT, truncated Large T; sT, small T, MHC-I, Major Histocompatibility Complex Class I; TLR-9, Toll-like receptor 9; TCR, T-cell receptor). Created in BioRender.com.

Figure 3

HIV-1 and HERV-K HML-2 interaction in the process of carcinogenesis: HIV-1 Tat protein leads to the upregulation of rec and np9, and gag expression through transcription factors NF-κB and NF-AT respectively. Also, HIV-1 Tat protein leads to the inhibition of monocytes and stimulation in differentiated macrophages through syncytin-1 expression. (HIV-1, Human Immunodeficiency Virus 1; HERV-K HML-2, Human Endogenous Retrovirus HML-2). Created in BioRender.com.

Figure 4

Oncogenic mechanisms mediated through HERVs and selected examples of their implications in cancers. (HERV, Human Endogenous Retrovirus; MDS, Myelodysplastic Syndrome; TLR, Toll-like Receptor). Created in BioRender.com.