Animal model for ultraviolet radiation-induced melanoma: platyfish-swordtail hybrid.

Abstract

Sunlight exposure is strongly indicated as one of the important etiologic agents in human cutaneous malignant melanoma. However, because of the absence of good animal models, it has not been possible to estimate the wavelengths or wavelength regions involved. We have developed a useful animal model from crosses and backcrosses of platyfish (Xiphophorus maculatus) and swordtails (Xiphophorus heUeri).Two strains of these fish are susceptible to invasive melanoma induction by exposure to filtered radiation from sunlamps in the wavelength ranges A > 290 nm and A > 304 nm. Multiple exposures on 5-20 consecutive days beginning on day 5 after birth or a single exposure of =200 J/(m2 day) of A > 304 nm result in a tumor prevalence of 20% to 40% at 4 months of age compared with a background rate of 12% in one strain and 2% in another. Exposure of the fish to visible light after UV exposure reduces the prevalence to background. The melanomas are similar in many respects to mammalian melanomas, as judged by light and electron microscopy. The genetics of the crosses determined by others and the high sensitivity of the hybrids to melanoma induction indicate that the UV radiation probably inactivates the one tumor repressor gene (or a small number of tumor repressor genes) in the hybrid fish. The small size of the animals and their high susceptibility to melanoma induction make them ideal for action spectroscopy.Agents that cause a decrease in stratospheric ozone would cause an increase in UV-B (A = 280-320 nm) intensities at the earth's surface without appreciably changing the longer UV or visible intensities of light. Melanoma among the white population of the United States and Europe is increasing dramatically as a function of time, probably as a result of changing lifestyles (1). The relation between latitude and melanoma mortality suggests that there is a correlation between the average solar radiation and mortality from malignant melanoma. However, it is not known which parts of the solar spectrum can plausibly be related to the increasing mortality because, although sunlight exposure seems to be an essential component in melanoma incidence, it is not the only one. Body areas most exposed to light are not the primary locations of melanomas as they are for basal and squamous cell carcinomas. There is good evidence that UV-B is tumorigenic in animals (2) and can cause neoplastic transformation in vitro (3). Four types of experiment indicate that light energy absorbed in DNA can cause cellular damage leading to tumors: (i) the tumorigenicity of fish cells as a result of UV-irradiation in vitro can be photoreactivated (4)-a process that monomerizes UV-induced cyclobutane pyrimidine dimers in DNA; (ii) the wavelengths effective in neoplastic transformation in vitro are those absorbed by DNA (5); (iii) transformation in vitro by UV is photoreactivable (6); and (iv) xeroderma pigmentosum individuals are defective in the ability to repair UV damages in their DNA and are extraordinarily sensitive to cancer induction, inc...

Comparative structure and characterization of a CDKN2 gene in a Xiphophorus fish melanoma model

“…Melanomas occur in backcross ®sh as the result of speci®c hybrid matings, thus minimizing potential environmental e ects in genetic studies. Alternatively, hybrids can be created which are generally more susceptible than parental ®sh to melanoma induction by chemical compounds (such as N-methyl-N-nitrosourea (MNU)), or radiation (X-ray, UV; Nairn et al, 1996a,b;Schwab et al, 1978;Setlow et al, 1989Setlow et al, , 1993.…”

“…A similar phenomenon of phenotypic enhancement and melanoma formation is evident in derived backcross hybrids to X. helleri in this case as well. This model also has proven to be amenable to UV induction of melanomas (Nairn et al, 1996a,b;Setlow et al, 1989Setlow et al, , 1993. Genetic mapping within the Xiphophorus LG V region using combined isozyme, RFLP, and AP-PCR/RAPD protocols has been initiated in order to clone the DIFF tumor suppressor gene (Kazianis et al, 1996(Kazianis et al, , 1998bMorizot et al, 1991).…”

Ultraviolet radiation and cutaneous malignant melanoma

“…Removal of UV-induced pyrimidine dimers by exposure to photoreactivating light greatly reduces tumor formation in Xiphophorus hybrids, implicating UV-induced DNA damage in melanomagenesis. Further studies by Setlow and colleagues using different UV wavebands have suggested a role for UVA radiation in the formation of melanoma in Xiphophorus (Setlow et al, 1989;Kusewitt and Ley, 1996). However, the Xiphophorus hybrid fish system is ultimately limited by its evolutionary distance from mammals.…”

“…Exposure of some Xiphophorus hybrids to UV radiation of wavelengths between 290 and 400 nm markedly enhances melanomagenesis (Setlow et al, 1989(Setlow et al, , 1993Setlow and Woodhead, 1994). This Xiphophorus hybrid system, which is amenable to genetic manipulation and demonstrates full progression from black spots to metastatic disease, has provided a number of notable insights.…”

The specific activation of gadd45 following UVB radiation requires the POU family gene product N-oct3 in human melanoma cells

“…The subsequent guanine oxidation is considered as potentially mutagenic. Experimental studies performed on animals have revealed that UVA can participate in the induction of melanomas (Setlow et al, 1989;Wolf et al, 1994). Furthermore, epidemiological data have shown that exposition to UVA constitutes a risk factor for melanoma (Wang et al, 2001;Westerdahl et al, 2000).…”