Metastatic cutaneous melanoma promoted by ultraviolet radiation in mice with transgene-initiated low melanoma susceptibility.
An inbred-strain (C57BL/6) transgenic (Tyr-SV40E) mouse model of ultraviolet radiation (UVR)-induced metastatic cutaneous melanoma was produced without the use of chemical carcinogens and without resulting in other skin malignancies. Expression of this transgene occurs specifically in melanocytic-lineage cells. In untreated hemizygous mice of transgenic line 12 there are no skin melanomas, and the oncogenic sequence, which is expressed at a very low level, functions solely as a weak initiating stimulus. UVR [including 65% ultraviolet B (280-320 nm wavelength)] supplied the necessary promoting stimulus leading to melanomas. Of various trial protocols, eight were successful and involved exposure of 112 mice for a limited time on each of 3-10 days starting at 2-3 days of age and totalling 1.1-3.7 J/cm2 UVR. Fourteen of these animals developed a total of 15 invasive skin melanomas on the head and body, arising between 37-115 weeks of age and, therefore, often after a relatively long latency. The tumors were melanotic and in five of the mice they yielded macrometastases in regional and distant sites. The single most favorable protocol (1.9 J/cm2 total UVR, at 0.38 J/cm2/day for 5 days starting at 3 days of age) led to the highest incidence of melanoma (5 of 19 mice) and one of the lowest mortality rates (2 of 19). No melanomas occurred in UVR-treated nontransgenic C57BL/6 controls. Benign skin keratoacanthomas arose and often regressed in treated transgenic as well as nontransgenic mice. This new transgenic mouse model introduces many novel possibilities for experimental analysis of the melanoma-promoting mechanisms of UVR and also of the ability of specific genetic changes to impede or facilitate the UVR effect.
Kelsall
S R
SR
Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
Mintz
B
B
D000818:Animals; D005260:Female; D008297:Male; D008545:Melanoma / Q000473:pathology / Q000556:secondary*; D008548:Melanosis / Q000209:etiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009381:Neoplasms, Radiation-Induced / Q000473:pathology / Q000556:secondary*; D012878:Skin Neoplasms / Q000473:pathology*; D014466:Ultraviolet Rays