Epidermal barrier defects link atopic dermatitis with altered skin cancer susceptibility

Elife. 2014 May 5;3:e01888. doi: 10.7554/eLife.01888.

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.

Keywords: cancer; eczema; skin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 9,10-Dimethyl-1,2-benzanthracene
  • Animals
  • Carcinoma, Squamous Cell / chemically induced
  • Carcinoma, Squamous Cell / genetics
  • Carcinoma, Squamous Cell / immunology
  • Carcinoma, Squamous Cell / metabolism
  • Carcinoma, Squamous Cell / pathology
  • Carcinoma, Squamous Cell / prevention & control*
  • Cell Communication
  • Cell Differentiation
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / immunology
  • Cell Transformation, Neoplastic / metabolism*
  • Cell Transformation, Neoplastic / pathology
  • Cytokines / blood
  • Dermatitis, Atopic / genetics
  • Dermatitis, Atopic / immunology
  • Dermatitis, Atopic / metabolism*
  • Dermatitis, Atopic / pathology
  • Disease Models, Animal
  • Epidermis / immunology
  • Epidermis / metabolism*
  • Epidermis / pathology
  • Keratinocytes / immunology
  • Keratinocytes / metabolism
  • Membrane Proteins / deficiency*
  • Membrane Proteins / genetics
  • Mice, 129 Strain
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Nude
  • NK Cell Lectin-Like Receptor Subfamily K / metabolism
  • Papilloma / chemically induced
  • Papilloma / genetics
  • Papilloma / immunology
  • Papilloma / metabolism
  • Papilloma / pathology
  • Papilloma / prevention & control*
  • Permeability
  • Plakins / deficiency*
  • Plakins / genetics
  • Protein Precursors / deficiency*
  • Protein Precursors / genetics
  • Signal Transduction
  • Skin Neoplasms / chemically induced
  • Skin Neoplasms / genetics
  • Skin Neoplasms / immunology
  • Skin Neoplasms / metabolism
  • Skin Neoplasms / pathology
  • Skin Neoplasms / prevention & control*
  • Tetradecanoylphorbol Acetate
  • Time Factors

Substances

  • Cytokines
  • Klrk1 protein, mouse
  • Membrane Proteins
  • NK Cell Lectin-Like Receptor Subfamily K
  • Plakins
  • Ppl protein, mouse
  • Protein Precursors
  • envoplakin
  • 9,10-Dimethyl-1,2-benzanthracene
  • involucrin
  • thymic stromal lymphopoietin
  • Tetradecanoylphorbol Acetate