The genetic control of chemically and radiation-induced skin tumorigenesis: a study with carcinogenesis-susceptible and carcinogenesis-resistant mice.
Outbred carcinogenesis-resistant (Car-R) and carcinogenesis-susceptible (Car-S) mouse lines were generated by phenotypic selection for resistance or susceptibility to two-stage skin carcinogenesis. These two Car mouse lines differ by >100-fold in susceptibility. In the present study, we tested the hypothesis that a subset of genetic loci responsible for susceptibility or resistance to chemical skin tumorigenesis may also be involved in radiation-induced skin tumorigenesis. Skin tumorigenesis was tested in groups of Car-S/R mice after X-ray initiation and 12-O-tetradecanoylphorbol-13-acetate (TPA) promotion. We found that ionizing radiation can initiate skin tumors in Car-S mice but not in Car-R mice. In Car-S mice, the most effective radiation doses (6 and 10 Gy given in four fractions) gave a threefold increase in tumor multiplicity and a twofold increase in tumor incidence compared to a TPA-only control group. We performed a molecular analysis of Hras gene mutations in skin tumors of Car-S mice induced by X-ray initiation/TPA promotion or by TPA promotion alone. The most notable difference emerging from the comparison of these mutation patterns is the high incidence ( approximately 50%) of papillomas lacking Hras gene mutations in X-ray-initiated/TPA-promoted papillomas compared to 13% in papillomas induced by TPA alone, suggesting that lack of Hras gene mutations is a consistent feature of radiation-induced papillomas.
Pazzaglia
Simonetta
S
Division of Protection of Man and the Ecosystems, ENEA CR-Casaccia, Rome, Italy. pazzaglia@casaccia.enea.it
Mancuso
Mariateresa
M
Rebessi
Simonetta
S
Di Majo
Vincenzo
V
Tanori
Mirella
M
Biozzi
Guido
G
Covelli
Vincenzo
V
Saran
Anna
A
D000818:Animals; D011905:Genes, ras / Q000235:genetics; D020022:Genetic Predisposition to Disease; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009154:Mutation; D009381:Neoplasms, Radiation-Induced / Q000235:genetics*; D012878:Skin Neoplasms / Q000235:genetics*; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity; D014965:X-Rays
D013755:Tetradecanoylphorbol Acetate