The scope of viral causation of human cancers: interpreting virus density from an evolutionary perspective

Abstract

Most known oncogenic viruses of humans use DNA as their genomic material. Research over the past quarter century has revealed that their oncogenicity results largely from direct interference with barriers to oncogenesis. In contrast to viruses that have been accepted causes of particular cancers, candidate viral causes tend to have fewer viral than cellular genomes in the tumours. These low viral loads have caused researchers to conclude that the associated viruses are not primary causes of the associated cancers. Consideration of differential survival, reproduction and infiltration of cells in a tumour suggest, however, that viral loads could be low even when viruses are primary causes of cancer. Resolution of this issue has important implications for human health because medical research tends to be effective at preventing and controlling infectious diseases. Mathematical models may clarify the problem and help guide future research by assessing whether low viral loads are likely outcomes of the differential survival, reproduction, and infiltration of cells in a tumour and, more generally, the extent to which viruses contribute to cancer. This article is part of the theme issue ‘Silent cancer agents: multi-disciplinary modelling of human DNA oncoviruses’.

Identifying key questions in the ecology and evolution of cancer

“…It is likely that the proportion of cancers with infectious causations is currently being underestimated. For example, viruses can cause tumours in which only a low proportion of cells are infected (1% of tumour cells are Epstein–Barr virus‐positive) (Ewald & Swain Ewald, 2019). If a criterion based on a low viral load is used to rule out an infectious cause, it is therefore possible that the number of cancers with underlying infectious agents is being underestimated due to our limited understanding of how symbionts drive oncogenesis (Dheilly et al, 2019; Jacqueline et al, 2017).…”

“…Infectious agents are known to abrogate barriers to cancer such as cell‐cycle arrest, apoptosis, telomerase regulation for non‐stem cells, cell adhesion for metastatic cancers and asymmetric division for stem cell cancers that block oncogenesis when they are in place (Ewald & Swain Ewald, 2014). In addition, infectious agents also disrupt processes that retard but do not block oncogenesis, such as restrictions of resources, vulnerability to immunological defences and regulation of cell division rates (Ewald & Swain Ewald, 2014, 2019). As a consequence, infectious agents can promote tumour formation and malignancy and cause the death of the host (Ewald & Swain Ewald, 2019; Plummer et al, 2016).…”

“…As a consequence, infectious agents can promote tumour formation and malignancy and cause the death of the host (Ewald & Swain Ewald, 2019;Plummer et al, 2016). It is likely that the proportion of cancers with infectious causations is currently being underestimated.…”

Human Mammary Tumor Virus, Human Papilloma Virus, and Epstein-Barr Virus Infection Are Associated With Sporadic Breast Cancer Metastasis

“…This low viral ratio might result from selective destruction of the infected tumor cells; asymmetric transfer of viral genome during cellular division may also be another reason of low infected cells in the tumor. 40 Herein, laser microdissection was used to get a reliable and enriched population of tumor cells. We examined the prevalence of EBV, HPV, and MMTV in 100 paraffin-embedded tissue samples from Jordanian breast cancer patients alongside a possible association with their clinical and pathologic parameters.…”

Towards a multi-level and a multi-disciplinary approach to DNA oncovirus virulence

“…In this issue, (i) Murall and Alizon [33] analyse the evolutionary trade-offs associated with the viral oncoprotein functions that on the one hand promote viral replication by stimulating cellular replication, but on the other hand may decrease viral fitness by facilitating immune targeting or by leading to a dead-end of a cancer. Further, (ii) Ewald and Swain Ewald [34] elaborate on the possibility that many other cancers could also be of infectious origin, revisiting the adage of Francisco Duran-Reynals from early last century, when saying that failure to demonstrate infectious virus in a tumour does not mean that a virus was not involved [35], and claiming that the roles of the cellular stroma and the immune system may prevent the identification of the viral oncogenic agent in the invasive, mature presentation of the cancer.…”