A definitive role of ornithine decarboxylase in photocarcinogenesis

Excessive exposure of solar ultraviolet (UV) radiation, particularly its UV B component, to human skin is the major cause for more than a million new c ases of cutaneous malignancies diagnosed annually in the United States. Pho tocarcinogenesis, like other cancers, is a multistep process that includes initiation and promotion. A proper understanding of the molecular events oc curring during the tumor promotion phase of photocarcinogenesis could lead to the development of novel approaches for the management of skin cancer. U sing a transgenic mouse model (K5/ODC mice), which overexpresses the enzyme ornithine decarboxylase (ODC) in hair follicle keratinocytes, we studied t he role of this gene in photocarcinogenesis. A single UVB-exposure of 180 m J/cm(2) to the transgenic mice resulted in a minimal increase in bifold ski n thickness and ODC activity. However, in SKH-1 hairless mice, the most com mon and highly sensitive model for photocarcinogenesis, and in littermate n ontransgenic mice, increases in skin thickness and ODC activity were substa ntial. In long-term experiments, mice were exposed to 180 mJ/cm(2) Of UVB r adiation three times a week for 2 weeks (tumor-initiating dose). At 30 week s after this treatment, in two independent experiments, 40% of the K5/ODC t ransgenic mice exposed to UVB were found to develop epidermal tumors. The t umors were histologically verified as benign papillomas and squamous cell c arcinomas. interestingly, 100% of the transgenic mice also developed >20 pi gmented cysts/mouse, which contained keratinocyte material with increased k eratinocytic melanization. Under similar UVB-exposure protocol, the nontran sgenic littermates or SKH-1 hairless mice did not develop tumors or pigment ed cysts for up to 50 weeks. Oral consumption of a-difluoromethylornithine, an irreversible specific inhibitor of ODC, in the drinking water (1% w/v) to the transgenic mice resulted in complete prevention of UVB-mediated tumo rigenesis and a substantial decrease in the formation of pigmented cysts (< 10 per mouse). These data establish a definitive role of ODC in the promoti on phase of photocarcinogenesis.