Cutaneous Papillomaviruses and Non-melanoma Skin Cancer: Causal Agents or Innocent Bystanders?

Mice are the experimental tool of choice for the majority of immunologists and the study of their immune responses has yielded tremendous insight into the workings of the human immune system. However, as 65 million years of evolution might suggest, there are significant differences. Here we outline known discrepancies in both innate and adaptive immunity, including: balance of leukocyte subsets, defensins, Toll receptors, inducible NO synthase, the NK inhibitory receptor families Ly49 and KIR, FcR, Ig subsets, the B cell (BLNK, Btk, and lambda5) and T cell (ZAP70 and common gamma-chain) signaling pathway components, Thy-1, gammadelta T cells, cytokines and cytokine receptors, Th1/Th2 differentiation, costimulatory molecule expression and function, Ag-presenting function of endothelial cells, and chemokine and chemokine receptor expression. We also provide examples, such as multiple sclerosis and delayed-type hypersensitivity, where complex multicomponent processes differ. Such differences should be taken into account when using mice as preclinical models of human disease.

  Nonmelanoma skin cancer (NMSC) is the most common cancer affecting white-skinned individuals and the incidence is increasing worldwide. This systematic review brings together 75 studies conducted over the past half century to look at geographical variations and trends worldwide in NMSC, and specifically incidence data are compared with recent U.K. cancer registry data. Following the development of a comprehensive search strategy, an assessment tool was adapted to look at the methodological quality of the eligible studies. Most of the studies focused on white populations in Europe, the U.S.A. and Australia; however, limited data were available for other skin types in regions such as Africa. Worldwide the incidence for NMSC varies widely with the highest rates in Australia [>1000/100, 000 person-years for basal cell carcinoma (BCC)] and the lowest rates in parts of Africa (< 1/100, 000 person-years for BCC). The average incidence rates in England were 76·21/100, 000 person-years and 22·65/100, 000 person-years for BCC and squamous cell carcinoma (SCC), respectively, with highest rates in the South-West of England (121·29/100, 000 person-years for BCC and 33·02/100, 000 person-years for SCC) and lowest rates by far in London (0·24/100, 000 person-years for BCC and 14·98/100, 000 person-years for SCC). The incidence rates in the U.K. appear to be increasing at a greater rate when compared with the rest of Europe. NMSC is an increasing problem for health care services worldwide. This review highlights a requirement for prevention studies in this area and the issues surrounding incomplete NMSC registration. Registration standards of NMSC should be improved to the level of other invasive disease. © 2012 The Authors. BJD © 2012 British Association of Dermatologists.

Summary Human papillomaviruses (HPVs) have evolved over millions of years to propagate themselves in a range of different animal species including humans. Viruses that have co‐evolved slowly in this way typically cause chronic inapparent infections, with virion production in the absence of apparent disease. This is the case for many Beta and Gamma HPV types. The Alpha papillomavirus types have however evolved immunoevasion strategies that allow them to cause persistent visible papillomas. These viruses activate the cell cycle as the infected epithelial cell differentiates in order to create a replication competent environment that allows viral genome amplification and packaging into infectious particles. This is mediated by the viral E6, E7, and E5 proteins. High‐risk E6 and E7 proteins differ from their low‐risk counterparts however in being able to drive cell cycle entry in the upper epithelial layers and also to stimulate cell proliferation in the basal and parabasal layers. Deregulated expression of these cell cycle regulators underlies neoplasia and the eventual progression to cancer in individuals who cannot resolve high‐risk HPV infection. Most work to date has focused on the study of high‐risk HPV types such as HPV 16 and 18, which has led to an understanding of the molecular pathways subverted by these viruses. Such approaches will lead to the development of better strategies for disease treatment, including targeted antivirals and immunotherapeutics. Priorities are now focused toward understanding HPV neoplasias at sites other than the cervix (e.g. tonsils, other transformation zones) and toward understanding the mechanisms by which low‐risk HPV types can sometimes give rise to papillomatosis and under certain situations even cancers. Copyright © 2015 John Wiley & Sons, Ltd.