Epidemiological studies support a link between cumulative sun exposure and cutaneous squamous cell carcinoma (SCC) development. However, the presumed effects of extended ultraviolet light B (UVB) exposure on tumorigenesis in the sexes have not been formally investigated. We examined differences in ultimate tumorigenesis at 25 weeks in mice exposed to UVB for either 10 or 25 weeks. Additionally, we investigated the effect of continued UVB exposure on the efficacy of topical treatment with anti-inflammatory (diclofenac) or antioxidant (C E Ferulic or vitamin E) compounds on modulating tumorigenesis. Vehicle-treated mice in the 25-week UVB exposure model exhibited an increased tumor burden and a higher percentage of malignant tumors compared to mice in the 10-week exposure model, which correlated with increases in total and mutant p53-positive epidermal cells. Only topical diclofenac decreased tumor number and burden in both sexes regardless of UVB exposure length. These data support the commonly assumed but not previously demonstrated fact that increased cumulative UVB exposure increases the risk of UVB-induced SCC development and can also affect therapeutic efficacies. Our study suggests that cessation of UVB exposure by at-risk patients may decrease tumor development and that topical NSAIDs such as diclofenac may be chemopreventive. 1. Introduction Epidemiological studies where patients self-report the amount of sun they have been exposed to over their lifetime have been the main source of the described link between cumulative, lifetime sunlight exposure and the development of cutaneous squamous cell carcinoma. While informative, with patients historically developing these lesions in their seventies, these self-reports may not accurately reflect the actual lifetime exposure history. Interestingly, we could not find any controlled studies reporting the effects of the length of lifetime UVB exposure on the extent of tumor development. Skin carcinogenesis experiments utilizing animal models, especially hairless mice, have contributed greatly to understanding how skin tumorigenesis depends on the wavelength of UV radiation, dose, and time [1]. The Skh-1 hairless mouse model has proven to be an appropriate and accepted model for experimental skin carcinogenesis [2]. Because the Skh-1 mice are hairless, tumors can be easily observed and their progression was tracked over time with relatively no discomfort for the mice. Importantly, after chronic UV exposure, shaved, haired mice can develop fibrosarcomas originating from the dermis [3], whereas the induction
References
[1]
F. R. de Gruijl, “Action spectrum for photocarcinogenesis,” Recent Results in Cancer Research, vol. 139, pp. 21–30, 1995.
[2]
F. R. de Gruijl and P. D. Forbes, “UV-induced skin cancer in a hairless mouse model,” BioEssays, vol. 17, no. 7, pp. 651–660, 1995.
[3]
F. Stenback, “Life history and histopathology of ultraviolet light-induced skin tumors,” National Cancer Institute Monograph, vol. NO 50, pp. 57–70, 1978.
[4]
F. Benavides, T. M. Oberyszyn, A. M. VanBuskirk, V. E. Reeve, and D. F. Kusewitt, “The hairless mouse in skin research,” Journal of Dermatological Science, vol. 53, no. 1, pp. 10–18, 2009.
[5]
J. M. Thomas-Ahner, B. C. Wulff, K. L. Tober, D. F. Kusewitt, J. A. Riggenbach, and T. M. Oberyszyn, “Gender differences in UVB-induced skin carcinogenesis, inflammation, and DNA damage,” Cancer Research, vol. 67, no. 7, pp. 3468–3474, 2007.
[6]
T. A. Wilgus, A. T. Koki, B. S. Zweifel, D. F. Kusewitt, P. A. Rubal, and T. M. Oberyszyn, “Inhibition of cutaneous ultraviolet light B-mediated inflammation and tumor formation with topical celecoxib treatment,” Molecular Carcinogenesis, vol. 38, no. 2, pp. 49–58, 2003.
[7]
F. R. de Gruijl and J. C. van der Leun, “Development of skin tumors in hairless mice after discontinuation of ultraviolet irradiation,” Cancer Research, vol. 51, no. 3, pp. 979–984, 1991.
[8]
K. Togsverd-Bo, C. M. Lerche, T. Poulsen, M. Hoedersdal, and H. C. Wulf, “Reduced ultraviolet irradiation delays subsequent squamous cell carcinomas in hairless mice,” Photodermatology Photoimmunology and Photomedicine, vol. 25, no. 6, pp. 305–309, 2009.
[9]
J. Ramos, J. Villa, A. Ruiz, R. Armstrong, and J. Matta, “UV dose determines key characteristics of nonmelanoma skin cancer,” Cancer Epidemiology Biomarkers and Prevention, vol. 13, no. 12, pp. 2006–2011, 2004.
[10]
E. M. Burns, K. L. Tober, J. A. Riggenbach et al., “Preventative topical diclofenac treatment differentially decreases tumor burden in male and female Skh-1 mice in a model of UVB-induced cutaneous squamous cell carcinoma,” Carcinogenesis, vol. 34, no. 2, pp. 370–377.
[11]
E. M. Burns, K. L. Tober, J. A. Riggenbach, D. F. Kusewitt, G. S. Young, and T. M. Oberyszyn, “Differential effects of topical vitamin e and C e ferulic(R) treatments on ultraviolet light B-induced cutaneous tumor development in skh-1 mice,” PLoS ONE, vol. 8, no. 5, Article ID e63809, 2013.
[12]
C. W. Dunnett and R. Crisafio, “The operating characteristics of some official weight variation tests for tablets,” The Journal of pharmacy and pharmacology, vol. 7, no. 5, pp. 314–327, 1955.
[13]
J. C. Hsu, “The factor analytic approach to simultaneous inference in the general linear model,” Journal of Computational and Graphical Statistics, vol. 1, no. 2, pp. 151–168, 1992.
[14]
H. Rebel, L. O. Mosnier, R. J. W. Berg et al., “Early p53-positive foci as indicators of tumor risk in ultraviolet-exposed hairless mice: kinetics of induction, effects of DNA repair deficieney, and p53 heterozygosity,” Cancer Research, vol. 61, no. 3, pp. 977–983, 2001.
[15]
H. J. van Kranen and F. R. de Gruijl, “Mutations in cancer genes of UV-induced skin tumors of hairless mice,” Journal of Epidemiology, vol. 9, supplement 6, pp. S58–S65, 1999.
