METASTATIC PHENOTYPE OF MOUSE-HUMAN MELANOMA CELL HYBRIDS IS ASSOCIATED WITH THE PRESENCE OF CHROMOSOME-17 FROM HIGHLY METASTATIC HUMAN-MELANOMA CELLS

We have previously shown that in interspecific mouse-human melanoma ce ll hybrids obtained by fusion of nonmetastatic mouse with metastatic h uman melanoma cells, the metastatic phenotype predominates. The purpos e of this study was to identify human chromosome(s) which could be res ponsible for conferring metastatic potential upon nonmetastatic mouse melanoma cells and therefore harbor the genes important for the metast atic properties of human melanoma cells. Seven mouse-human melanoma hy brids were examined; five were derived from the fusion of nonmetastati c (C19) and metastatic (C3) mouse K-1735 melanoma clones with highly m etastatic clone (C15) of human melanoma A375 and the two others had as a human partner a nonmetastatic clone (Cls) of the A375 melanoma. The hybrids were examined during segregation of human chromosomes in vitr o and in vivo for metastatic properties in nude mice and for the retai ning human chromosomes. In the hybrid H7, which demonstrated the highe st metastatic potential, the presence of human chromosomes was studied by GTG-banding and by fluorescence in situ hybridization (FISH) analy sis. In the other hybrids, only FISH detection of human chromosomes wa s applied. All hybrids derived from nonmetastatic mouse and metastatic human melanoma cells demonstrated metastatic properties from early pa ssages, when they contained the majority of the human chromosomes. The ir metastatic phenotype remained stable during further segregation of most of the human chromosomes except for 17. Chromosome 17 was retaine d most consistently in all examined hybrids. However, the metastatic p henotype of the hybrids was associated only with the presence of chrom osome 17 from the metastatic human donor cells. This chromosome was al so found in almost 100% of cells recovered from lung metastases derive d from the hybrid cells. In one lung metastasis developed from the H7 hybrid, chromosome 17 was detected as the sole human chromosome and th ese cells preserved the acquired high metastatic properties. Based on these results we conclude that human chromosome 17 from metastatic mel anoma cells (A375 C15), when functional in the mouse genetic backgroun d, can be sufficient to render the recipient nonmetastatic mouse cells to a fully malignant phenotype. Additional data suggest that this abi lity might be related to the expression of the mutated human p53 gene.