CHANGES IN EXPRESSION OF PUTATIVE ANTIGENS ENCODED BY PIGMENT GENES IN MOUSE MELANOMAS AT DIFFERENT STAGES OF MALIGNANT PROGRESSION

Cutaneous melanomas of Tyr-SV40E transgenic mice (mice whose transgene consists of the tyrosinase promotor fused to the coding regions of si mian virus 40 early genes) strikingly resemble human melanomas in thei r development and progression. Unlike human melanomas, the mouse tumor s all arise in genetically identical individuals, thereby better enabl ing expression of specific genes to be characterized in relation to ad vancing malignancy. The products of pigment genes are of particular in terest because peptides derived from these proteins have been reported to function as autoantigens with immunotherapeutic potential in some melanoma patients. However, the diminished pigmentation characteristic of many advanced melanomas raises the possibility that some of the re levant products may no longer be expressed in the most malignant cells . We have therefore investigated the contributions of several pigment genes in melanotic vs, relatively amelanotic components of primary and metastatic mouse melanomas. The analyses reveal marked differences wi thin and among tumors in levels of mRNAs and proteins encoded by the w ild-type alleles at the albino, brown, slaty, and silver loci. Tyrosin ase (the protein encoded by the albino locus) was most often either ab sent or undetectable as melanization declined. The protein encoded by the slaty locus (tyrosinase-related protein 2) was the only one of tho se tested that was clearly present in all the tumor samples. These res ults suggest that sole reliance on targeting tyrosinase-based antigens might selectively favor survival of more malignant cells, whereas tar geting the ensemble of the antigens tested might contribute toward a m ore inclusive and effective antimelanoma strategy.