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 and Fiona M. Watt ()
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Esther Hoste: Cancer Research UK Cambridge Research institute, Li Ka Shing Centre
Esther N. Arwert: Cancer Research UK Cambridge Research institute, Li Ka Shing Centre
Rohit Lal: Cancer Clinical Academic Group, Guy's and St Thomas' NHS Trust, Bermondsey Wing, Guy's Hospital, Great Maze Pond
Andrew P. South: Ninewells Hospital and Medical School, University of Dundee
Julio C. Salas-Alanis: Medicine School, University of Monterrey
Dedee F. Murrell: St George Hospital, University of New South Wales, Sydney, New South Wales 2217, Australia
Giacomo Donati: Cancer Research UK Cambridge Research institute, Li Ka Shing Centre
Fiona M. Watt: Centre for Stem Cells and Regenerative Medicine, King’s College London

Nature Communications, 2015, vol. 6, issue 1, 1-10

Abstract: 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 wound-induced 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.

Date: 2015
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DOI: 10.1038/ncomms6932

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