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.
Highlights
The association between tissue damage, chronic inflammation and cancer is well known
We have found a previously unknown role for Toll-like receptor (TLR)-5, the receptor for bacterial flagellin, in skin tumour formation, both in the InvEE mouse model and in wild-type (WT) mice treated with chemical carcinogens
We further show that TLR-5 plays a role in upregulation of the alarmin HMGB1 (High Mobility Group Box 1) in woundinduced mouse tumours and demonstrate that HMGB1 is elevated in tumours of Recessive Dystrophic Epidermolysis Bullosa (RDEB) patients
Summary
The association between tissue damage, chronic inflammation and cancer is well known. Malignancies at wound sites are often overlooked in chronic ulcers in diabetic and elderly patients[5] Another context in which the association between skin wounding and cancer is well established is Recessive Dystrophic Epidermolysis Bullosa (RDEB). Wounded human skin and psoriatic lesions are characterized by misexpression of b1 integrin extracellular matrix receptors in the differentiating epidermal cell layers, and consequent upregulation of extracellular signal-regulated kinaseMAP-kinase signalling[7] When this is modelled in transgenic mice by expression of constitutively active MAP-kinase kinase 1 under the control of the involucrin promoter (InvEE mice), there is chronic skin inflammation and epidermal hyperproliferation, and mice develop benign tumours (papillomas) on wounding[8,9]. We further show that TLR-5 plays a role in upregulation of the alarmin HMGB1 (High Mobility Group Box 1) in woundinduced mouse tumours and demonstrate that HMGB1 is elevated in tumours of RDEB patients
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