In mice, 7,12-dimethylbenz[a]anthrancene (DMBA) and the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) are frequently used as skin model tumour initiator and promoter, respectively. The sequential administration of DMBA and TPA leads to the appearance of a large number of benign papillomas, of which some convert later into invasive squamous cell carcinomas (SCC). At the molecular level, initiation of carcinogenesis in mouse skin consists in the mutational activation of the Ha-ras oncoprotein. HA-RAS mutations are rare in human SCC, but HA-RAS-mutated tumours appear in melanoma patients treated with B-raf inhibitors, indicating that initiated, HA-RAS-mutated stem cells also reside in human skin. Similarly, UV-induced human SCC shows footprint mutations in the tumour suppressor gene TP53, which are also observed in UV-induced mouse SCC. Strong species differences exist with respect to phorbol ester-mediated tumour promotion. While certain mouse strains are very susceptible, other rodent species are much less sensitive. Likewise, humans appear to be much more resistant to phorbol ester-mediated skin toxicity. Papilloma formation as a result of a chemical insult is uncommon in men, questioning the relevance of this preneoplastic lesion for humans. However, skin tumorigenesis in the experimental situation and in humans appears to follow common molecular mechanisms, even though there are species differences in the morphological correlates to the preneoplastic state. Therefore, the author recommended not simply labelling them as irrelevant for human risk assessment.
Authors: Schwarz, Michael; Muenzel, Peter A.; Braeuning, Albert. ;Full Source: Archives of Toxicology 2013, Ahead of Print (English) ;