[Cyclooxygenases in the skin]

Cyclooxygenases (COX)-1 and COX-2 catalyse the key steps of prostaglandin biosynthesis and are the major target for non-steroidal anti-inflammatory drugs. In general, COX-1 but not COX-2 is expressed in healthy tissues of adults. After incision or acute irritant dermatitis, COX-2 is induced transiently. The development of UV-induced erythema and edema as well as of skin tumours is significantly governed by COX-2 activity. Squamous cell carcinomas and actinic keratoses are prominent examples of epithelial tumours with COX-2 overexpression in the tumour parenchyma, inflammatory infiltrate and associated vessels. According to multi-stage carcinogenesis studies in mouse skin and experiments with transgenic mice, there is a causal relationship between aberrant COX-2 expression and activity in the epithelium and tumour promotion and tumour progression. The transgenic overexpression of COX-2 causes an "autopromoted" skin phenotype, i.e. it dramatically sensitizes the tissue for the development of squamous cell carcinomas. Vice versa, the genetic ablation of COX-2, as well as of COX-1, results in a reduced tumour burden in murine skin. A major mechanism by which COX-2 contributes to epidermal tumour formation seems to be the disturbance of terminal keratinocyte differentiation. Because of these data, selective COX-2 inhibitors are ranked among the most promising agents for skin cancer prevention and therapy.