Innate sensing of microbial products promotes wound-induced skin cancer

Esther Hoste, Esther N. Arwert, Rohit Lal, Andrew P. South, Julio C. Salas-Alanis, Dedee F. Murrell, Giacomo Donati, Fiona M. Watt

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53 Citations (Scopus)

Abstract

The association between tissue damage, chronic inflammation and cancer is well known. However, the underlying mechanisms are unclear. Here we characterize a mouse model in which constitutive epidermal extracellular-signal-regulated kinase-MAP-kinase signalling results in epidermal inflammation, and skin wounding induces tumours. We show that tumour incidence correlates with wound size and inflammatory infiltrate. Ablation of tumour necrosis factor receptor (TNFR)-1/-2, Myeloid Differentiation primary response gene 88 or Toll-like receptor (TLR)-5, the bacterial flagellin receptor, but not other innate immune sensors, in radiosensitive leukocytes protects against tumour formation. Antibiotic treatment inhibits, whereas injection of flagellin induces, tumours in a TLR-5-dependent manner. TLR-5 is also involved in chemical-induced skin carcinogenesis in wild-type mice. Leukocytic TLR-5 signalling mediates upregulation of the alarmin HMGB1 (High Mobility Group Box 1) in woundinduced papillomas. HMGB1 is elevated in tumours of patients with Recessive Dystrophic Epidermolysis Bullosa, a disease characterized by chronic skin damage. We conclude that in our experimental model the combination of bacteria, chronic inflammation and wounding cooperate to trigger skin cancer.

Original languageEnglish
Article number5932
JournalNature Communications
Volume6
DOIs
Publication statusPublished - 9 Jan 2015

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Hoste, E., Arwert, E. N., Lal, R., South, A. P., Salas-Alanis, J. C., Murrell, D. F., Donati, G., & Watt, F. M. (2015). Innate sensing of microbial products promotes wound-induced skin cancer. Nature Communications, 6, [5932]. https://doi.org/10.1038/ncomms6932