Viruses in Cancers of the Digestive System: Active Contributors or Idle Bystanders?

Abstract

The human virome, which is a collection of all the viruses that are present in the human body, is increasingly being recognized as an essential part of the human microbiota. The human gastrointestinal tract and related organs (e.g., liver, pancreas, and gallbladder)-composing the gastrointestinal (or digestive) system-contain a huge number of viral particles which contribute to maintaining tissue homeostasis and keeping our body healthy. However, perturbations of the virome steady-state may, both directly and indirectly, ignite/sustain oncogenic mechanisms contributing to the initiation of a dysplastic process and/or cancer progression. In this review, we summarize and discuss the available evidence on the association and role of viruses in the development of cancers of the digestive system.

Keywords: EBV; HBV; HCV; HPV; Wnt/β-catenin; colorectal cancer; eukaryotic viruses; p53; phages; virome.

Figure 1

Virus-mediated modulation of the Wnt/β-catenin pathway. (A) When Wnt signalization is off, β-catenin is phosphorylated via the β-catenin destruction complex and subsequently degraded by the proteasome. (B) When a Wnt ligand binds a Wnt receptor (Frizzled), the β-catenin destruction complex is inactive, and β-catenin accumulates and enters the nucleus, where it modulates the transcription of target genes. (C) When infecting a cell, a virus may interact with some of the Wnt pathway components (e.g., the β-catenin destruction complex), leading to the accumulation of β-catenin and persistent transcription of its target genes, even in the absence of a Wnt ligand.

Figure 2

Example of virus-mediated carcinogenesis. A virus can infect a eukaryotic cell (A) and randomly insert its genetic information into the host genome via the lysogenic life cycle (B,D). If the viral genetic material falls in a non-coding region, the modified host DNA continues to function normally until the cell reaches senescence and is removed by apoptosis (C). However, the integration of the viral genome into a region coding a tumor suppressor gene (such as p53 or Rb), can affect cell proliferation/survival and, in combination with other DNA modifications, contribute to uncontrollable cell division, which may result in dysplasia and eventually, cancer (E).