Changing Stem Cell Dynamics during Papillomavirus Infection: Potential Roles for Cellular Plasticity in the Viral Lifecycle and Disease

Abstract

Stem cells and cellular plasticity are likely important components of tissue response to infection. There is emerging evidence that stem cells harbor receptors for common pathogen motifs and that they are receptive to local inflammatory signals in ways suggesting that they are critical responders that determine the balance between health and disease. In the field of papillomaviruses stem cells have been speculated to play roles during the viral life cycle, particularly during maintenance, and virus-promoted carcinogenesis but little has been conclusively determined. I summarize here evidence that gives clues to the potential role of stem cells and cellular plasticity in the lifecycle papillomavirus and linked carcinogenesis. I also discuss outstanding questions which need to be resolved.

Keywords: HPV; cellular plasticity; stem cells.

Figure 1

Potential mechanisms through which papillomavirus infection may contribute to the development of stem-like cells and cancer stem cells. (a) Targeting cellular tumor suppressors for degradation: retinoblastoma protein (pRb) has been shown to bind both sex determining region Y-box 2 (Sox2), and octamer-binding transcription factor 4 (Oct4) leading to repression of pluripotency [56]. p53 Has been shown to directly bind and suppress transcription from the Nanog promoter [55]. Both pRb and p53 have been shown to be important gatekeepers during cellular reprogramming, and their absence significantly facilitates the process [50,51,53,56]. (b) Transcriptional upregulation of histone modifying enzymes: Upregulation of lysine (K)-specific demethylase 6A and 6B (KDM6A and KDM6B, respectively) mediated by the E7 oncogene of HPV16 leads to a reduction of repressive H3K27 chromatin marks and downstream activation of targets such as Hox genes [62,63]; (c) Transcriptional upregulation of stem cell-related transcription factors: the viral oncogenes E6 and E7 of high-risk types have been linked to the upregulation of pluripotency associated transcription factors—Oct4 [61], Hes family basic helix-loop-helix transcription factor 1 (Hes1) [67]. Infection with cutaneous papillomaviruses has also been linked to the upregulation of stem cell related genes [30,64]. (d) Post-transcriptional control of stem cell related transcription factors has also been demonstrated: E7 has been reported to bind Oct4 and act as a transcriptional co-activator [60]. Both E6 and E7 have been shown to transcriptionally, post-transcriptionally and post-translationally regulate Kruppel-like factor 4 (Klf4) (e.g., via hyposumoylation) leading to modified Klf4 activity in infected keratinocytes [58]. The upregulation of stemness related genes has been most frequently attributed to the viral oncogenes E6 and E7 but the full mechanisms underlying some of these effects have yet to be elucidated. Furthermore, the impact of the re-expression or modulation of stemness related genes in the viral lifecycle and carcinogenesis is still poorly understood.

Figure 2

Model of changes in stem cells during papillomavirus infection and carcinogenesis. (a) Papillomaviruses can gain access to the basal layer of stratified epithelia via microwounds. Following attachment to the basement membrane, the virus can infect committed or stem cells in the basal layer of the epithelium. As the epithelium heals, infected cells are subject to changes due to the expression of early gene products and local inflammatory signals linked to infection and the regenerative response. (b) Stem cells or stem-like cells (with at least some atypical features) detected during infection and viral maintenance may be derived from infected stem cells or committed cells which have been reprogrammed. (c) Cancer stem cells may likewise be derived from infected tissue stem cells or from drastically de-differentiated committed cells.