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

Abstract

The metastatic stability of clones, which were derived from the murine UV-2237 fibrosarcoma and which exhibit low or high metastatic 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 ofexperimental pulmonary metastases after intravenous injection into syngeneic C3H-mice. In contrast, subelones 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.

Melanoma Metastasis

“…Moreover, in highly metastatic clones, the rate of spontaneous mutation was several times that of low metastatic clones. [25] These results are in accord with the hypothesis that tumor progression occurs as a result of acquired genetic alterations. Similar data have been reported for other neoplasms.…”

Why cancer at the primary site and in the lymph nodes contributes to the risk of cancer death

“…Apparently, the probability of an event of lethal spread, per cell, is the same regardless of the site from which the cancer cells originate. It often has been wondered whether mutation at the time of spread is a requirement for metastasis [8][9][10][11][12][13][14][15][16][17] ; however, following the reasoning outlined previously, 3 the values for the probabilities of metastatic spread of breast carcinoma, renal cell carcinoma, and melanoma cells presented here are difficult to reconcile with such genetic change: First, the value of the probability of lethal spread for the smallest melanomas (0.1 mm), at approximately 1 event of spread for every 500 cells, is many orders of magnitude greater than that expected for a genetic change. Second, the probability of metastatic spread per cell from the primary site declines as the tumor increases in size.…”

Spread of human cancer cells occurs with probabilities indicative of a nongenetic mechanism

“…These values indicate that the spread of human breast cancer and melanoma cells is unlikely to occur by a mechanism requiring mutation at the time of spread. There has been much uncertainty as to whether metastasis requires mutation at the time of spread (Cifone and Fidler, 1981;Fidler, 1983;Sobel, 1990;Welch et al, 2000;Yokota, 2000;Bernards and Weinberg, 2002;Couzin, 2003;Bernards, 2003;Van't Veer and Weigelt, 2003;Yang et al, 2004). Mutations have a number of characteristic features, in terms of the rates of their occurrence and other qualities, which are diagnostic: mutations are rare, a phenotype conferred on a cell by mutation is inherited by the progeny of the cell, and the rates of the appearance of phenotypes caused by mutations either remains constant over time for those phenotypes requiring only a single mutation, or increase in frequency for those phenotypes requiring the accumulation of multiple mutations.…”