Prevention of MEK1-associated tumours in murine epidermis by inhibition of interleukin-1

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1541 Background: Pro-inflammatory cytokines have a role in facilitating a pro-tumourigenic microenvironment in chronic inflammatory diseases and may identify targets for chemoprevention. The host microenvironment has a role in driving the malignant capacity of tumours, determining whether they develop into squamous cell cancers or benign tumours. For example, suprabasal β1 integrin expression, as seen in some squamous cell carcinomas, activates extra-cellular signal regulated kinase (ERK) in basal and suprabasal keratinocytes and profoundly affects the susceptibility of the underlying proliferating cells to chemical carcinogenesis. I present the results of experiments using transgenic mice, hereafter referred to as InvEE, that express activated mitogen activated protein kinase kinase-1 (MEK1) in suprabasal layers of the epidermis resulting in constitutive ERK overexpression and results in increased keratinocyte expression of interleukin- 1a (IL-1 alpha), triggers epidermal hyperplasia, skin inflammation and benign tumours. Methods: I developed a protocol for inducing tumour formation in InvEE mice by full-thickness skin punch biopsy. I negated the affect of IL-1 alpha activation of inflammatory cells by generating InvEE bone marrow chimeras using MyD-88-/- mice or litter-mate InvEE mice as a control. InvEE/InvEE and InvEE/Myd- 88-/- chimeric mice were wounded and observed for tumour formation for 60 days. The experiment was conducted twice and the number of tumours in each group was analysed using a chi-squared test. Results: Spontaneous benign tumours occurred in 27 of 295 (9%) InvEE mice correlating with cutaneous injury. Punch-biopsy wounding induced tumours after 3–4 weeks in 37 of 92 (40%) InvEE mice compared to no tumours in 40 (0%) wild-type litter-mates (p<0.0001). The percentage of wound-induced tumours in bone-marrow chimeras of InvEE/InvEE and InvEE/MyD-88-/- was 40% and 8% respectively (p<0.005). Resident inflammatory cells demonstrated differential responses to wounding in InvEE/MyD-88-/- chimeric skin. Conclusions: This study demonstrated that inhibition of IL-1 alpha signalling from MEK1-activated keratinocytes prevented tumour formation in a chronic inflammatory microenvironment. No significant financial relationships to disclose.