Genetic predisposition of transgenic mouse melanocytes to melanoma results in malignant melanoma after exposure to a low ultraviolet B intensity nontumorigenic for normal melanocytes.
Tyr-SV40E transgenic mice are susceptible to melanoma due to simian virus 40 oncogenic sequences specifically expressed in pigment cells. Skin melanomas form relatively late. Therefore, melanocyte cell lines have been established from very young transgenic animals, when they showed no skin lesions, so that the spontaneous and gradual progress of the cells toward tumorigenesis could be characterized under culture conditions in which wild-type cells of the same inbred strain remain untransformed. Melanocytes of an in vitro transgenic line were irradiated with very low intensities of ultraviolet B (UVB) (280- to 320-nm wavelength) light at culture passages when the cells had not achieved anchorage independence. After a single exposure to 0.7 mJ/cm2 of UVB radiation, the cells became anchorage independent and formed foci at confluence; however, cells propagated from the foci were not tumorigenic. After one exposure to 1.75 mJ/cm2, more numerous and larger foci resulted, and the cells grown from them yielded malignant melanomas in graft hosts. Wild-type melanocytes were not transformed at these UVB doses. At least two genetic changes contributing to malignant conversion--in addition to the initiating effect of the transgene--are likely to have occurred, one change leading to anchorage independence and another to further progress toward malignancy. Cells at these stages provide an opportunity to isolate the relevant genes and identify any molecular defects attributable to UVB. Tumorigenesis after a very low UVB dose in cells where an initiating stimulus is already present suggests that some other stimulus, such as a gene or a carcinogen, might lead to melanoma in conjunction with exposure to relatively little UVB.
Larue
L
L
Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, PA 19111.
Dougherty
N
N
Mintz
B
B
D000818:Animals; D002448:Cell Adhesion; D002454:Cell Differentiation; D002455:Cell Division; D002470:Cell Survival / Q000528:radiation effects; D008544:Melanocytes / Q000528:radiation effects*; D008546:Melanoma, Experimental / Q000209:etiology* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009381:Neoplasms, Radiation-Induced / Q000235:genetics*; D009857:Oncogenes; D013539:Simian virus 40 / Q000235:genetics; D014466:Ultraviolet Rays