Mice With Genetically Determined High Susceptibility to Ultraviolet (UV)-Induced Immunosuppression Show Enhanced UV Carcinogenesis

• Published in: Journal of investigative dermatology Vol. 121; no. 5; pp. 1175 - 1181
• Main Authors: Noonan, Frances P., Konrad Muller, H., Fears, Thomas R., Kusewitt, Donna F., Johnson, Tracy M., De Fabo, Edward C.
• Format: Journal Article
• Language: English
• Published: Danvers, MA Elsevier Inc 01.11.2003; Nature Publishing; Elsevier Limited
• Subjects: Animals; Biological and medical sciences; Dermatology; Dose-Response Relationship, Radiation; Female; Genetic Predisposition to Disease; Immune Tolerance - radiation effects; Immunohistochemistry; immunosuppression; Male; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Neoplasms, Radiation-Induced - etiology; Neoplasms, Radiation-Induced - immunology; risk factor; skin cancer; Species Specificity; Survival Analysis; ultraviolet radiation; Ultraviolet Rays - adverse effects; ultraviolet radiation; skin cancer; immunosuppression; risk factor; Vertebrata; Immunosuppression; Ultraviolet radiation; Mammalia; skin cancer/risk factor/ultraviolet radiation/immunosuppression; Mouse; Dermatology; Animal; Rodentia; Genetics; Carcinogenesis
• ISSN: 0022-202X; 1523-1747
• DOI: 10.1046/j.1523-1747.2003.12560.x

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 F1 hybrid mice CB6F1 males with high susceptibility to UV immunosuppression and a BALB/c X-chromosome and B6CF1 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 m2) 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 CB6F1 mice than in the B6CF1 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 CB6F1 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.