The role of Langerhans cells in squamous cell carcinoma
Epithelial surfaces, such as the skin, provide an interface with the environment and as such are repeatedly exposed to a variety of toxins and mutagens. This is reflected in the fact that 90% of human cancers arise in epithelial tissues. Amongst the cells of the skin are a type of dendritic cell known as Langerhans cells (LCs) which are generally believed to internalise, process and present antigens from abnormal cells to T cells, triggering an immune response and limiting carcinogenesis. However a surprising result was achieved when mice with no LCs were used in a model of squamous cell carcinoma (SCC) development (1). The model involves mice undergoing a single cutaneous exposure to a polyaromatic hydrocarbon (PAH) known to initiate cancer called 7,12-dimethylbenz(α)anthracene (DMBA) followed by repeated exposure to a promoter chemical. In wild type mice this leads to the development of multiple papillomas, some of which develop into SCC. LC negative mice are resistant to this cutaneous carcinogenesis in a T cell independent manner. A paper published in Science this week looks into the mechanism behind this (2).
Modi et al. showed that wild type mice had three times higher levels of DNA damage, in the keratinocytes of skin 24 hours post exposure to DMBA compared to LC negative mice. Furthermore wild type mice accumulated oncogenic Hras mutations at a greater rate than LC negative animals. It is actually a metabolite of DMBA that causes DNA damage and so the effect of applying this metabolite to the skin was assessed. Comparable levels of DNA damage were seen in both wild type and LC negative mice, suggesting that LCs are involved in processing DMBA to its mutagenic form. This processing of DMBA involves interaction of the chemical with the aryl hydrocarbon receptor which increases the transcription of certain enzymes which then process DMBA to an intermediate metabolite which is hypothesised to enter keratinocytes, where further processing results in the formation of a highly mutagenic product which causes DNA damage. It was confirmed that human LCs are capable of taking up and metabolising DMBA in a similar way to seen in murine LCs.
This study suggests an important role for LCs in the pathophysiology of SCC independent of their role in the immune response. A pathway, presumably present to reduce the toxicity of environmental toxins, in the case of PAHs actually results in a metabolite with a greater mutagenic potential than the original toxin. As PAHs are widely found in industrial pollution this may be of relevance to the development of human SCCs.
1. Modi, B. G., Neustadter, J., Binda, E., Lewis, J., Filler, R. B., Roberts, S. J., Kwong, B. Y., Reddy, S., Overton, J. D., Galan, A., Tigelaar, R., Cai, L., Fu, P., Shlomchik, M., Kaplan, D. H., Hayday, A. & Girardi, M. Langerhans cells facilitate epithelial DNA damage and squamous cell carcinoma. Science 2012; 335: 104-8.
2. Strid, J., Roberts, S. J., Filler, R. B., Lewis, J. M., Kwong, B. Y., Schpero, W., Kaplan, D. H., Hayday, A. C. & Girardi, M. Acute upregulation of an NKG2D ligand promotes rapid reorganization of a local immune compartment with pleiotropic effects on carcinogenesis. Nat Immunol (2008); 9:146-54.
Story image from Wikimedia Commons.