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Epidermal barrier defects link atopic dermatitis with altered skin cancer susceptibility
Sara Cipolat1, Esther Hoste1, Ken Natsuga2
1Centre for Stem Cells and Regenerative Medicine, King's College London, London, United Kingdom Cancer Research UK Cambridge Research Institute, Cambridge, United Kingdom.
Abstract:
Atopic dermatitis can result from loss of structural proteins in the outermost epidermal layers, leading to a defective epidermal barrier. To test whether this influences tumour formation, we chemically induced tumours in EPI-/- mice, which lack three barrier proteins-Envoplakin, Periplakin, and Involucrin. EPI-/- mice were highly resistant to developing benign tumours when treated with 7,12-dimethylbenz(a)anthracene (DMBA) and 12-O-tetradecanoylphorbol-13-acetate (TPA). The DMBA response was normal, but EPI-/- skin exhibited an exaggerated atopic response to TPA, characterised by abnormal epidermal differentiation, a complex immune infiltrate and elevated serum thymic stromal lymphopoietin (TSLP). The exacerbated TPA response could be normalised by blocking TSLP or the immunoreceptor NKG2D but not CD4+ T cells. We conclude that atopy is protective against skin cancer in our experimental model and that the mechanism involves keratinocytes communicating with cells of the immune system via signalling elements that normally protect against environmental assaults.DOI: http://dx.doi.org/10.7554/eLife.01888.001.
Insights
Mice with a defective skin barrier, mimicking atopic dermatitis, showed resistance to benign tumor formation. This protective effect involved thymic stromal lymphopoietin (TSLP) and NKG2D signaling, suggesting atopy can prevent skin cancer.
Area of Science:
- Dermatology
- Immunology
- Oncology
Background:
- Atopic dermatitis is linked to a defective epidermal barrier due to loss of structural proteins.
- The role of epidermal barrier defects in tumor formation is not fully understood.
Purpose of the Study:
- To investigate if a defective epidermal barrier influences skin tumor development.
- To explore the mechanisms underlying this influence.
Main Methods:
- Chemically induced skin tumors in EPI-/- mice lacking Envoplakin, Periplakin, and Involucrin.
- Administered 7,12-dimethylbenz(a)anthracene (DMBA) and 12-O-tetradecanoylphorbol-13-acetate (TPA) to induce tumors.
- Analyzed epidermal differentiation, immune infiltrate, and serum thymic stromal lymphopoietin (TSLP) levels.
- Investigated the effects of blocking TSLP, NKG2D, and CD4+ T cells.
Main Results:
- EPI-/- mice were highly resistant to developing benign tumors after DMBA/TPA treatment.
- EPI-/- skin showed an exaggerated atopic response to TPA, with abnormal differentiation, immune infiltrate, and elevated TSLP.
- Blocking TSLP or NKG2D normalized the exacerbated TPA response, while blocking CD4+ T cells did not.
Conclusions:
- Atopic dermatitis, characterized by a defective epidermal barrier, confers protection against skin cancer in this experimental model.
- The protective mechanism involves keratinocyte-immune cell communication via signaling elements like TSLP and NKG2D.