Rapid phenotype variation in cells derived from lung metastases of KHT fibrosarcoma

We have established previously that intravenously derived metastatic variants are generated in KHT fibrosarcoma cells at an effective rate of 10(-5)/cell/generation. To study the properties of these variants further, we examined several lines of KHT fibrosarcoma cells obtained from experimental lung metastases. When tested using an experimental metastasis assay, some of the lines were highly metastatic, relative to parental lines, but these highly metastatic phenotypes were often rapidly lost as the lines were grown in vitro, and both decreases and increases in metastatic ability were observed. In another set of experiments, lines obtained by 10 serial selections of experimental lung metastases without intervening in vitro growth between passages were also analyzed. Again, while highly metastatic phenotypes were observed in some instances, they did not persist beyond 1 or 2 in vivo passages, and the series as a whole failed to reveal a persistent increase in ability to form experimental metastases. We conclude from these experiments that although metastatic variants are generated at high rates in KHT cell lines, the phenotype is lost at even higher rates, and metastatic variants represent only a small proportion of the tumor cell population. Thus, it appears that in this system rapid phenotypic variation may play an important role in the metastatic process.