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 dysplasias) and squamous cell carcinomas (SCCs) develop in one quarter of human neonatal foreskins grafted onto recombinase-activating gene-1-knockout mice treated once with 7,12-dimethylbenz[a]anthracene (DMBA) followed by chronic intermediate-range ultraviolet (UV) B light irradiation. The goals of this study were to determine if a longer UVB exposure followed by further observation would increase the number of precancers and invasive cancers and to evaluate whether this model results in changes in p53 expression and cell proliferation similar to those seen in sun-damaged normal skin, actinic keratoses, and SCCs. The treatment consisted of a single dose of DMBA followed by 500 J/m2 UVB radiation administered three times weekly for at least 5 mo. Histologic changes (cysts, hyperplasias, precancers, and/or invasive cancers) were seen in 24 of 25 treated xenografts but not in controls. Ten of 25 grafts (40%) had two or more histological changes, and two human SCCs developed. 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 developed squamous precancer or SCC of human origin, and 44% (eight of 18) developed melanocytic hyperplasia or melanoma. The change from moderate dysplasias to SCC required longer UV exposure (median, 11 mo), and 5 mo more observation than did the development of mild dysplasias (median UV exposure, 7 mo; median DMBA to death time, 12 mo). There was a direct correlation between both p53 expression and cell proliferation and the degree of histologic alteration both in squamous epithelial and melanocytic cells.
Sauter
E R
ER
The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
Klein-Szanto
A J
AJ
Atillasoy
E
E
Montone
K T
KT
Goodrow
T
T
Binder
R L
RL
Seykora
J T
JT
Herlyn
M
M
D015127:9,10-Dimethyl-1,2-benzanthracene; D000328:Adult; D000818:Animals; D034961:Antigens, Nuclear; D014408:Biomarkers, Tumor / Q000032:analysis; D002273:Carcinogens; D002294:Carcinoma, Squamous Cell / Q000209:etiology* / Q000473:pathology; D002455:Cell Division / Q000502:physiology; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000528:radiation effects; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D008297:Male; D008544:Melanocytes / Q000473:pathology / Q000528:radiation effects*; D051379:Mice; D009381:Neoplasms, Radiation-Induced / Q000209:etiology* / Q000473:pathology; D009687:Nuclear Proteins / Q000096:biosynthesis; D011230:Precancerous Conditions / Q000209:etiology* / Q000473:pathology; D012867:Skin / Q000473:pathology / Q000528:radiation effects*; D012878:Skin Neoplasms / Q000209:etiology* / Q000473:pathology; D016038:Skin Transplantation; D013997:Time Factors; D014183:Transplantation, Heterologous; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis; D014466:Ultraviolet Rays / Q000009:adverse effects*
D034961:Antigens, Nuclear; D014408:Biomarkers, Tumor; D002273:Carcinogens; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; D016159:Tumor Suppressor Protein p53; C064658:RAG-1 protein; D015127:9,10-Dimethyl-1,2-benzanthracene