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Nat Commun. 2015 Jan 9;6:5932. doi: 10.1038/ncomms6932.

Innate sensing of microbial products promotes wound-induced skin cancer.

Author information

1
1] Cancer Research UK Cambridge Research institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK [2] Centre for Stem Cells and Regenerative Medicine, King's College London, 28th Floor, Tower Wing, Guy's Campus, London SE1 9RT, UK.
2
Cancer Research UK Cambridge Research institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.
3
Cancer Clinical Academic Group, Guy's and St Thomas' NHS Trust, Bermondsey Wing, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.
4
1] Division of Cancer Research, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, UK [2] Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
5
Basic Science Department, Medicine School, University of Monterrey, Nuevo Leon 64849, Mexico.
6
Department of Dermatology, St George Hospital, University of New South Wales, Sydney, New South Wales 2217, Australia.
7
Centre for Stem Cells and Regenerative Medicine, King's College London, 28th Floor, Tower Wing, Guy's Campus, London SE1 9RT, UK.

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.

PMID:
25575023
PMCID:
PMC4338544
DOI:
10.1038/ncomms6932
[Indexed for MEDLINE]
Free PMC Article

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