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Solar ultraviolet (UV) radiation-induced immune suppression has been considered as a risk factor for nonmelanoma and melanoma skin cancers. The immunoregulatory cytokine interleukin (IL)-12 reverses UV-induced immune suppression in mice. Additionally, the demonstration of significant anti-tumor activity of IL-12 in several preclinical animal tumor models has stimulated interest in the therapeutic use of this cytokine. To examine the role of IL-12 in UV radiation-induced skin carcinogenesis, we generated IL-12 knockout (KO) mice on a C3H/HeN background and subjected them to a photocarcinogenesis protocol. Mice were exposed to UV (180mJ/cm2) radiation three times a week for 35 weeks and the susceptibility of IL-12 KO mice against UV-induced skin cancer was determined and compared with their wild-type counterparts. The development of UV-induced tumors was more rapid and the tumor multiplicity and tumor size was significantly higher in IL-12 KO mice (p<0.05-0.001) than in their wild-type counterparts. Moreover, the rate of malignant transformation of UV-induced papillomas to carcinomas was higher in IL-12 KO mice in terms of carcinoma incidence (55%, p<0.001), carcinoma multiplicity (77%, p<0.001) and carcinoma size (81%, p<0.001) compared to their wild-type counterparts. Immunostaining, western blot analysis and gelatinolytic zymography revealed that the protein expression and activity of matrix metalloproteinase (MMP)-2 and MMP-9 were significantly higher (p<0.001) in UV-induced tumors and tumor-uninvolved skin of the IL-12 KO mice than their wild-types. Further, the expression of vascular endothelial growth factor and CD31 was higher in tumors of the IL-12 KO mice which may have greater role in tumor growth and angiogenesis. The fluorescence staining of CD31+ cells (a cell surface marker of endothelial cells) in skin tumors indicated that there was enhanced peritumoral vascular density and clusters and elongated structures of vessels in tumors of IL-12 KO mice compared to their wild-types. Taken together, these data indicate that IL-12-deficiency enhances UV-induced tumorigenesis and malignant transformation in mice, and that IL-12-deficient mice are more susceptible to UVB-induced pro-angiogenic stimuli than their wild-type counterparts. This study raises the possibility that in vivo stimulation or exogenous administration of IL-12 may prove beneficial in the prevention of solar UV radiation-induced skin cancer.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]