Langerhans Cells Facilitate Epithelial DNA Damage and Squamous Cell Carcinoma

Abstract

Polyaromatic hydrocarbons (PAHs) are prevalent, potent carcinogens, and 7,12-dimethylbenz[a]anthracene (DMBA) is a model PAH widely used to study tumorigenesis. Mice lacking Langerhans cells (LCs), a signatory epidermal dendritic cell (DC), are protected from cutaneous chemical carcinogenesis, independent of T cell immunity. Investigation of the underlying mechanism revealed that LC-deficient skin was relatively resistant to DMBA-induced DNA damage. LCs efficiently metabolized DMBA to DMBA-trans-3,4-diol, an intermediate proximal to oncogenic Hras mutation, and DMBA-treated LC-deficient skin contained significantly fewer Hras mutations. Moreover, DMBA-trans-3,4-diol application bypassed tumor resistance in LC-deficient mice. Additionally, the genotoxic impact of DMBA on human keratinocytes was significantly increased by prior incubation with human-derived LC. Thus, tissue-associated DC can enhance chemical carcinogenesis via PAH metabolism, highlighting the complex relation between immune cells and carcinogenesis.

The bright and the dark sides of activin in wound healing and cancer

“…This finding is in line with previous reports that demonstrate that activin A induces the differentiation of Langerhans cells from circulating and skinresident precursor cells , and that transgenic mice overexpressing follistatin in keratinocytes have a strongly reduced number of Langerhans cells (Stoitzner et al, 2005). As these cells promote skin carcinogenesis that is induced by DMBA and TPA, by metabolizing DMBA into a more mutagenic compound and thereby increasing DNA damage (Modi et al, 2012), their accumulation in the epidermis of activin-overexpressing mice could further contribute to the pro-tumorigenic phenotype.…”

Carcinogen-Induced Skin Tumor Development Requires Leukocytic Expression of the Transcription Factor Runx3

“…When LCs are absent, metabolic activation of chemical carcinogens (e.g., DMBA) that induce tumor initiation was impaired (37). Moreover, although DETC-depleted mice manifest higher susceptibility to DMBA/TPA tumorigenesis by themselves (27), combined depletion of DETCs and LCs retained the robust LCdeficient tumor-resistant phenotype (47).…”

“…These results suggested that although Runx3-expressing DCs were essential, they were not sufficient to furnish Runx3-null full tumor resistance. Modi and colleagues (37) showed that absence of epidermal LCs confers complete resistance to DMBA/TPAinduced tumorigenesis. Therefore, we evaluated the involvement of LCs in Runx3-null tumor resistance by immunostaining of epidermal sheets from na€ ve DC Runx3À/À ear skin and flow cytometry (Fig.…”

A review of the current state of the art of physiologically-based tests for measuring human dermal in vitro bioavailability of polycyclic aromatic hydrocarbons (PAH) in soil

“…It is important to recognise that the presence of foreign compounds in the skin can lead to localised effects e.g. Langerhan cells may increase the likelihood of carcinogenesis due to the metabolisation of dermally absorbed PAH (Modi et al, 2012); similar observations of the genotoxicity of benzo[a]pyrene have also been made for metablolisation by kerotinocytes (e.g. Brinkmann et al 2013).…”