Abstract
Viral infection is an indisputable causal factor for nearly 17% of all human cancers. However, the diversity and complexity of oncogenic mechanisms raises new questions as to the mechanistic role of viruses in cancer. Classical viral oncogenes have been identified for all tumor-associated viruses. These oncogenes can have multiple oncogenic activities that may or may not be utilized in a particular tumor cell. In addition, stochastic events, like viral mutation and integration, as well as heritable host susceptibilities and immune deficiencies are also implicated in tumorigenesis. A more contemporary view of tumor biology highlights the importance of evolutionary forces that select for phenotypes better adapted to a complex and changing environment. Given the challenges of prioritizing singular mechanistic causes, it may be necessary to integrate concepts from evolutionary theory and systems biology to better understand viral cancer-driving forces. Here, we propose that viral infection provides a biological “entropy” that increases genetic variation and phenotypic plasticity, accelerating the main driving forces of cancer cell evolution. Viruses can also influence the evolutionary selection criteria by altering the tumor microenvironment and immune signaling. Utilizing concepts from cancer cell evolution, population genetics, thermodynamics, and systems biology may provide new perspectives on viral oncogenesis and identify novel therapeutic strategies for treating viruses and cancer.
Highlights
Viruses have well-established causal roles in numerous human and animal cancers, collectively responsible for almost one fifth of all cancers [1, 2]
While the pathways of viral carcinogenesis are cellular, viruses do provide foreign genomes and gene products that create new interactions and pathways for oncogenesis. How do these viral products and viralspecific pathways work coordinately over time to overcome the many barriers to cellular carcinogenesis? What makes these seven viruses different from their non-oncogenic relatives? Here, we suggest that oncogenic viruses are unique in their ability to increase the adaptability and evolvability of infected cells, and that multiple perturbations over time enable formation of cancer cell fate choices
We further suggest that this be considered in terms of Shannon information theory, where viral genomes may be considered a source of signal noise enabling the freedom to find a lower energy state, or alternative gene regulatory network (GRN), such as the oncogenic state
Summary
Viruses have well-established causal roles in numerous human and animal cancers, collectively responsible for almost one fifth of all cancers [1, 2]. There are seven human viruses with strong epidemiological links to human cancers These include members of the high-risk human papillomavirus (HPVs), hepatitis viruses B and C (HBV and HCV), human gammaherpesviruses (HHV4/Epstein-Barr Virus (EBV) and HHV8/Kaposi’s Sarcoma-Associated Herpesvirus (KSHV), Merkel cell polyomavirus (MCPyV), and human T-cell leukemia virus I (HTLV-1). These oncoviruses represent members of vastly different families of virus, including DNA, RNA and retroviridae. Many non-cancer-causing viruses perturb these pathways and have similar viral-host interactions It is not fully understood what features confer viruses with oncogenic potential in human populations. We suggest that a more in-depth knowledge of virus-host interactions over the time-course of cancer evolution will provide a more complete understanding of viral oncogenesis
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