ULTRAVIOLET B-INDUCED SQUAMOUS EPITHELIAL AND MELANOCYTIC CELL CHANGES IN A XENOGRAFT MODEL OF CANCER DEVELOPMENT IN HUMAN SKIN

We previously demonstrated that precancers (actinic keratoses and dysp lasias) and squamous cell carcinomas (SCCs) develop in one quarter of human neonatal foreskins grafted onto recombinase-activating gene-1-kn ockout mice treated once with 7,12-dimethylbenz[a]anthracene (DMBA) fo llowed by chronic intermediate-range ultraviolet (UV) B light irradiat ion. The goals of this study were to determine if a longer UVB exposur e followed by further observation would increase the number of precanc ers and invasive cancers and to evaluate whether this model results in changes in p53 expression and cell proliferation similar to those see n in sun-damaged normal skin, actinic keratoses, and SCCs. The treatme nt consisted of a single dose of DMBA followed by 500 J/m(2) UVB radia tion administered three times weekly for at least 5 mo. Histologic cha nges (cysts, hyperplasias, precancers, and/or invasive cancers) were s een in 24 of 25 treated xenografts but not in controls. Ten of 25 graf ts (40%) had two or more histological changes, and two human SCCs deve loped. After seven or more months of UV exposure and a total time from DMBA treatment to killing of 12-18 mo, 83% (15 of 18) of specimens de veloped squamous precancer or SCC of human origin, and 44% (eight of 1 8) developed melanocytic hyperplasia or melanoma. The change from mode rate dysplasias to SCC required longer UV exposure (median, 11 mo), an d 5 mo more observation than did the development of mild dysplasias (m edian UV exposure, 7 mo; median DMBA to death time, 12 mo). There was a direct correlation between both p53 expression and cell proliferatio n and the degree of histologic alteration both in squamous epithelial and melanocytic cells. (C) 1998 Wiley-Liss, Inc.