Mice With Genetically Determined High Susceptibility to Ultraviolet (UV)-Induced Immunosuppression Show Enhanced UV Carcinogenesis
Noonan, FP and Muller, HK and Fears, TR and Kusewitt, DF and Johnson, TM and De Fabo, EC, Mice With Genetically Determined High Susceptibility to Ultraviolet (UV)-Induced Immunosuppression Show Enhanced UV Carcinogenesis, Investigative Dermatology, 121, (5) pp. 1175-1181. ISSN 0022-202X (2003) [Refereed Article]
To assess the premise that genetically determined differences in susceptibility to UV-induced immunosuppression are reflected in UV carcinogenesis, we investigated UV skin cancer induction in two strains of reciprocal F 1 hybrid mice CB6F 1 males with high susceptibility to UV immunosuppression and a BALB/c X-chromosome and B6CF 1 males with low susceptibility to UV immunosuppression and a C57BL/ 6 X-chromosome. Four experimental groups comprising both strains treated three times weekly with two UV regimens (daily doses incremented from 2.25 to 6 or 4. 5 to 12 kJ per m 2) were monitored for skin tumor development. Survival without a skin tumor differed over the four groups (p < 0.0001) and differed according to UV regimen within each strain (p < 0.0005). Differences between strains were significant for the higher dose (p = 0.03) but not for the lower dose (p = 0.19) of UV, suggesting a dose-strain interaction. Comparing the higher UV dose regimen to the lower UV dose regimen within a strain at three reference points, tumor-free survival was reduced significantly more (p < 0.05) in the CB6F 1 mice than in the B6CF 1 mice. Histologic assessment of all tumors revealed fibrosarcomas, squamous carcinomas, and mixed tumors. Immunohistochemistry of the mixed tumors for vimentin, keratin, and E-cadherin confirmed the presence of squamous and fibrosarcomatous elements. The enhanced susceptibility to UV carcinogenesis of CB6F 1 males treated with the higher UV pro-tocol was attributable to a significantly enhanced proportion (p < 0.005) of mixed tumors. Analysis of the data by comparing the proportion of animals tumor free at three reference time points confirmed a dose-strain interaction only in the development of mixed tumors, putatively the malignantly advanced carcinomas (p < 0.03). A dose-strain interaction was also observed for systemic UV immunosuppression of contact hypersensitivity (p < 0.025). These findings support the concept that genetic differences in susceptibility to UV-induced immunosuppression may be a risk factor for skin cancer.