MULTIPLE FEATURES OF ADVANCED MELANOMA RECAPITULATED IN TUMORIGENIC VARIANTS OF EARLY-STAGE (RADIAL GROWTH-PHASE) HUMAN-MELANOMA CELL-LINES- EVIDENCE FOR A DOMINANT PHENOTYPE

The vast majority of primary human cutaneous melanomas undergo a slow and gradual progression from a clinically indolent, curable radial gro wth phase (RGP) to a malignant vertical growth phase. We sought to dev elop a way of isolating genetically related malignant variants from a benign RGP human melanoma, called WM35. The parent and variants were t hen used as a model system to examine to what extent the expression of clinically and biologically relevant phenotypic features characterist ic of advanced melanomas are associated with (and thus perhaps causati ve of) such a malignant conversion. Such a model system could also be used as a means of eventually identifying genetic alterations and cell ular changes involved in the malignant switch in melanoma progression. To develop such a model, we subjected WM35 cells to retrovira inserti onal mutagenesis, which was followed by selection for progressive grow th of solid tumors in nude mice. Highly aggressive and phenotypically stable tumorigenic variants were derived which contained at least four integrated proviruses. In contrast to the parental WM35 cells, these cell lines expressed several phenotypic features characteristic of nat urally derived, advanced-stage malignant melanoma cells. Thus, in addi tion to tumor-forming ability in nude mice, the variants were growth f actor and anchorage independent, overexpressed the MUC18 adhesion mole cule, and lost responsiveness to the growth-inhibitory effect of sever al cytokines, including interleukin 6, transforming growth factor beta , interleukin 1 beta, and tumor necrosis factor-alpha. Tumorigenicity and ''multicytokine resistance'' were dominant traits since in somatic cell hybrids between the parental cells and a tumorigenic subline no suppressive effect of the former cell population was observed. These f indings suggest that one or more dominantly acting genetic alterations might be involved in this progression of RGP melanoma cells. The iden tity of such alterations remains to be determined.