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

Research output: Contribution to journalArticle

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Abstract

© 2015 Macmillan Publishers Limited. All rights reserved. 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

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Toll-Like Receptor 5
Skin Neoplasms
Tumors
Skin
tumors
cancer
Wounds and Injuries
Flagellin
products
Neoplasms
Extracellular Signal-Regulated MAP Kinases
Inflammation
mice
boxes
Epidermolysis Bullosa Dystrophica
Receptors, Tumor Necrosis Factor, Type II
Tumor Necrosis Factor Receptors
damage
Mitogen-Activated Protein Kinase Kinases
leukocytes

Cite this

Hoste, E., Arwert, E. N., Lal, R., South, A. P., Salas-Alanis, J. C., Murrell, D. F., ... Watt, F. M. (2015). Innate sensing of microbial products promotes wound-induced skin cancer. Nature Communications, 6, [5932]. https://doi.org/10.1038/ncomms6932
Hoste, Esther ; Arwert, Esther N. ; Lal, Rohit ; South, Andrew P. ; Salas-Alanis, Julio C. ; Murrell, Dedee F. ; Donati, Giacomo ; Watt, Fiona M. / Innate sensing of microbial products promotes wound-induced skin cancer. In: Nature Communications. 2015 ; Vol. 6.
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Hoste, E, Arwert, EN, Lal, R, South, AP, Salas-Alanis, JC, Murrell, DF, Donati, G & Watt, FM 2015, 'Innate sensing of microbial products promotes wound-induced skin cancer', Nature Communications, vol. 6, 5932. https://doi.org/10.1038/ncomms6932

Innate sensing of microbial products promotes wound-induced skin cancer. / Hoste, Esther; Arwert, Esther N.; Lal, Rohit; South, Andrew P.; Salas-Alanis, Julio C.; Murrell, Dedee F.; Donati, Giacomo; Watt, Fiona M.

In: Nature Communications, Vol. 6, 5932, 09.01.2015.

Research output: Contribution to journalArticle

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AB - © 2015 Macmillan Publishers Limited. All rights reserved. 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.

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Hoste E, Arwert EN, Lal R, South AP, Salas-Alanis JC, Murrell DF et al. Innate sensing of microbial products promotes wound-induced skin cancer. Nature Communications. 2015 Jan 9;6. 5932. https://doi.org/10.1038/ncomms6932