title: Innate sensing of microbial products promotes wound-induced skin cancer.
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.
authors.affiliation: 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.
authors.forename: Esther
authors.initials: E
authors.lastname: Hoste
authors.affiliation: Cancer Research UK Cambridge Research institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.
authors.forename: Esther N
authors.initials: EN
authors.lastname: Arwert
authors.affiliation: Cancer Clinical Academic Group, Guy's and St Thomas' NHS Trust, Bermondsey Wing, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.
authors.forename: Rohit
authors.initials: R
authors.lastname: Lal
authors.affiliation: 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.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: South
authors.affiliation: Basic Science Department, Medicine School, University of Monterrey, Nuevo Leon 64849, Mexico.
authors.forename: Julio C
authors.initials: JC
authors.lastname: Salas-Alanis
authors.affiliation: Department of Dermatology, St George Hospital, University of New South Wales, Sydney, New South Wales 2217, Australia.
authors.forename: Dedee F
authors.initials: DF
authors.lastname: Murrell
authors.affiliation: 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.
authors.forename: Giacomo
authors.initials: G
authors.lastname: Donati
authors.affiliation: Centre for Stem Cells and Regenerative Medicine, King's College London, 28th Floor, Tower Wing, Guy's Campus, London SE1 9RT, UK.
authors.forename: Fiona M
authors.initials: FM
authors.lastname: Watt
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D005260:Female; D005408:Flagellin / Q000378:metabolism; D024243:HMGB1 Protein / Q000378:metabolism*; D006410:Hematopoiesis; D006801:Humans; D007249:Inflammation / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D015398:Signal Transduction; D012867:Skin / Q000473:pathology; D012878:Skin Neoplasms / Q000276:immunology* / Q000382:microbiology*; D051198:Toll-Like Receptor 5 / Q000378:metabolism; D014947:Wounds and Injuries / Q000473:pathology
chemical_list: D000900:Anti-Bacterial Agents; D024243:HMGB1 Protein; C585491:HMGB1 protein, human; C582808:HMGB1 protein, mouse; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C495346:TLR5 protein, human; D051198:Toll-Like Receptor 5; D005408:Flagellin