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 ultra violet radiation (UVR)-induced metastatic cutaneous melanoma was produ ced without the use of chemical carcinogens and without resulting in o ther skin malignancies. Expression of this transgene occurs specifical ly in melanocytic-lineage cells. In untreated hemizygous mice of trans genic line 12 there are no skin melanomas, and the oncogenic sequence, which is expressed at a very low level, functions solely as a weak in itiating stimulus. UVR [including 65% ultraviolet B (280-320 nm wavele ngth)] supplied the necessary promoting stimulus leading to melanomas. Of various trial protocols, eight were successful and involved exposu re of 112 mice for a limited time on each of 3-10 days starting at 2-3 days of age and totalling 1.13.7 J/cm(2) UVR. Fourteen of these anima ls developed a total of 15 invasive skin melanomas on the head and bod y, arising between 37-115 weeks of age and, therefore, often after a r elatively long latency. The tumors were melanotic and in five of the m ice they yielded macrometastases in regional and distant sites. The si ngle most favorable protocol (1.9 J/cm(2) total UVR, at 0.38 J/cm(2)/d ay 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 contr ols. Benign skin keratoacanthomas arose and often regressed in treated transgenic as well as nontransgenic mice. This new transgenic mouse m odel introduces many novel possibilities for experimental analysis of the melanoma-promoting mechanisms of UVR and also of the ability of sp ecific genetic changes to impede or facilitate the UVR effect.