Viruses in colorectal cancer

Abstract

Increasing evidence suggests that microorganisms might represent at least highly interesting cofactors in colorectal cancer (CRC) oncogenesis and progression. Still, associated mechanisms, specifically in colonocytes and their microenvironmental interactions, are still poorly understood. Although, currently, at least seven viruses are being recognized as human carcinogens, only three of these – Epstein–Barr virus (EBV), human papillomavirus (HPV) and John Cunningham virus (JCV) – have been described, with varying levels of evidence, in CRC. In addition, cytomegalovirus (CMV) has been associated with CRC in some publications, albeit not being a fully acknowledged oncovirus. Moreover, recent microbiome studies set increasing grounds for new hypotheses on bacteriophages as interesting additional modulators in CRC carcinogenesis and progression. The present Review summarizes how particular groups of viruses, including bacteriophages, affect cells and the cellular and microbial microenvironment, thereby putatively contributing to foster CRC. This could be achieved, for example, by promoting several processes – such as DNA damage, chromosomal instability, or molecular aspects of cell proliferation, CRC progression and metastasis – not necessarily by direct infection of epithelial cells only, but also by interaction with the microenvironment of infected cells. In this context, there are striking common features of EBV, CMV, HPV and JCV that are able to promote oncogenesis, in terms of establishing latent infections and affecting p53‐/pRb‐driven, epithelial–mesenchymal transition (EMT)‐/EGFR‐associated and especially Wnt/β‐catenin‐driven pathways. We speculate that, at least in part, such viral impacts on particular pathways might be reflected in lasting (e.g. mutational or further genomic) fingerprints of viruses in cells. Also, the complex interplay between several species within the intestinal microbiome, involving a direct or indirect impact on colorectal and microenvironmental cells but also between, for example, phages and bacterial and viral pathogens, and further novel species certainly might, in part, explain ongoing difficulties to establish unequivocal monocausal links between specific viral infections and CRC.

Involvement of HHV-4 (Epstein–Barr Virus) and HHV-5 (Cytomegalovirus) in Inflammatory Bowel Disease and Colorectal Cancer: A Meta-Analysis

“…It is well known that HHV-4 can disrupt the cell cycle at several points, fostering the genesis of cancer and even metastasis [ 61 , 64 ]. For instance, the EBV-derived LMP1 disrupts several cellular signal pathways (such as NF-κB, PI 3 K, and MAPK) [ 65 ] and reduces the expression of E-cadherin [ 66 ], which is also targeted by HHV-4′s micro interfering RNAs, such as miR-BART9 [ 67 ].…”

Unusually high incidence of polyomavirus JC infection in the higher grade of colorectal cancer tissues in Taiwan

“…It is thought that the LT protein of polyomavirus contributes to viral transformation activity [ 34 , 35 ], and that β-catenin is stabilized by JCPyV LT protein [ 21 ], causing JCPyV to play a role in the progression of CRC [ 36 ]. Recently, increasing evidence suggests various pathogens represent risk factors in CRC oncogenesis [ 37 , 38 ]. Among these infectious agents, Epstein–Barr virus (EBV), human papillomavirus (HPV), and JCPyV, have been intensively studied [ 38 ].…”

“…Recently, increasing evidence suggests various pathogens represent risk factors in CRC oncogenesis [ 37 , 38 ]. Among these infectious agents, Epstein–Barr virus (EBV), human papillomavirus (HPV), and JCPyV, have been intensively studied [ 38 ]. However, some controversial data have also been reported [ 39 ].…”

Potential oncogenic role of human cytomegalovirus and histone deacetylase 3 expression in colorectal cancer

“…CMV DNA was detected in 11 % of the 56 formalin-fixed paraffin-embedded CRC by PCR [26]. A characteristic that implies the interaction between CMV and host cells derived from the intestine is still unknown, which could affect viral detection [12].…”

“…Despite not being a fully acknowledged oncogenic virus. [12]. Although CMV is widespread in the community, it is more significant when there is immune suppression during pregnancy [13].…”