Increasing metastatic potential is associated with increasing genetic instability of clones isolated from murine neoplasms

The metastatic stability of clones, which were derived from the murine UV-2237 fibrosarcoma and which exhibit low or high metastitic potential, was examined after 60-72 days of continuous growth in vitro and in vivo. Subclones of the high metastatic clone exhibited a 140-fold variation in the production of experimental pulmonary metastases after intravenous injection into syngeneic C3H^- mice. In contrast, subclones from the low metastatic clone varied only slightly (8-fold). Using cloned cells from three mouse tumors with differing metastatic potential, we determined the spontaneous mutation rates of cells with low or high metastatic capacities with respect to the selective genetic markers, 6-thiopurine resistance or ouabain resistance, or both. In all cases, cells with high metastatic potential had a 3- to 7-fold increase in the rate of mutation (per cell generation) at both genetic loci, as compared with their low metastatic but tumorigenic cell controls. These results support the hypothesis that the evolution of tumors from the benign to the malignant state could be the consequence of acquired genetic instability in the neoplastic cells.