Chapter 11 - Arsenic skin carcinogenesis: A prototypic model of chemical carcinogenesis featured with abnormal differentiation and aberrant immune responses

Abstract

The prevalence of human cancers, including skin, lung, and bladder, are increased in arsenism areas, where humans are exposed to inorganic arsenic (As) from drinking water. The skin is the most sensitive organ of chronic arsenic poisoning. Arsenic-induced skin cancers tend to be multiple and include Bowen’s disease (intraepidermal carcinoma in situ), squamous cell carcinoma (SCC), and basal cell carcinoma (BCC). Arsenic-induced Bowen’s disease (As-BD) is the main and early form of arsenic cancer, which may transform to invasive cancers after decades. Therefore, the dynamic process and mechanism underlying As-BD development provides a good model for investigating the early events in chemical carcinogenesis. Arsenic carcinogenesis remains unclear, but it apparently perturbs epidermal proliferation, differentiation, apoptosis, and immune activation. For epidermal differentiation, arsenic induces aberrant epidermal differentiation by suppressing Notch1 Signaling through transcriptional events. For epidermal proliferation, arsenic increases mitochondrial biogenesis, and induces p63 isoform and growth factor expression, leading to abnormal epidermal proliferation. For apoptosis, UVB (ultraviolet B) and arsenic, both of which are skin carcinogens, induce cell apoptosis, and they synergize in activation of different caspase cascades to enhance apoptosis. For immune activation, arsenic mediates aberrant immune responses by selectively inducing peripheral CD4+ T cell apoptosis and Langerhans cells migration. In reconstructed skin equivalent, blocking TNF-α release by arsenic-treated peripheral blood lymphocytes inhibits the development of the arsenical cancer-like pathology. We concluded that pathogenesis of the multiple and recrudescent arsenic-induced skin cancers includes not only the abnormal epidermal homeostasis, but also the aberrant immune responses in skin. This review provides a potential approach to prevention of chemical carcinogenesis in the early stage.