A model of human cancer metastasis: extensive spontaneous and artificial metastasis of a human pigmented melanoma and derived variant sublines in nude mice.

The extensive metastatic capacities in nude mice of variants of a human melanoma line, MeWo, were studied. BALB/c nude mice received subcutaneous implants of lung cubes impregnated in vitro with small numbers (less than 1,000) of MeWo cells as a result of previous in vitro coincubation. Such implants always resulted in lethal tumors, despite the fact that injection of dispersed 3 X 10(5) MeWo cells was normally required to obtain a tumor take. A BALB/c nude mouse that had received a MeWo lung cube implant was found to have numerous, large lung nodules 6 months after implantation. Transfer of the metastatic lung nodules to new recipients also led to the appearance of lung metastases. Cell lines established from such metastases, or from primary tumors that arose in nude mice implanted with MeWo-infiltrated cubes, showed a remarkable ability to colonize the lungs after iv injection, in contrast to the parent MeWo cells: Lungs were found to be engorged with hundreds of nodules, many, but not all, being melanotic. Widespread extrapulmonary metastases were also observed, but only after iv injection of MeWo sublines established from metastases. Karyotype analysis revealed that lung colonies established by iv cell injection had a near diploid (i.e., wild type) number of human chromosomes (mode: 44), whereas cell lines from spontaneous metastases possessed a near tetraploid number, a possible consequence of either selection or tumor progression in vivo. The results indicate that human tumor variants with unusually aggressive metastatic capabilities can be obtained in adult nude mice, similar in nature to some highly metastatic variants derived from mouse tumors (e.g., the B16 melanoma). The availability of such variants should be a valuable aid to study aspects of tumor cell heterogeneity, progression, and metastasis from a human cancer cell perspective.