High Metastatic Clones Research Articles

High-metastatic clones selected in vitro from a recent spontaneous BALB/c mammary adenocarcinoma cell line.

The metastatic TS/A line has been recently derived from a spontaneous BALB/c mammary tumor. When TS/A cells were cultured in 0.33 per cent agar, two morphologically distinct types of colonies were observed from which two sets of clones were obtained. E clones were derived from small, transparent colonies, whereas F clones were from large, thick, actively growing colonies. All the clones were tumorigenic in syngeneic BALB/c females. However, E clones showed higher ability than F clones to metastasize spontaneously to the lung. Comparison between E and F clones shows that the high level of spontaneous metastasization to the lung is associated with epithelial-like in vitro growth pattern, spontaneous dome formation and growth pattern in 0.33 per cent agar cultures. The ability to give rise to lung colonies following intravenous inoculation is not a predictive parameter for the spontaneous metastatic potential.

MHC imbalance and metastatic spread in Lewis lung carcinoma clones.

Imbalance in the Kb and Db region encoded molecules is observed in Lewis lung carcinoma clones. The uncloned metastatic population and the D122 high-metastatic clone show no expression of H-2Kb products, while the nonmetastatic A9 clone expresses Kb products. Twenty-nine new subclones of 3LL and A9 were analyzed for D-end and K-end membrane expression, primary growth rate and metastatic spread. We show that the imbalance in H-2Kb to H-2Db is correlated with metastatic properties of a given clone, but local tumor growth is not. A "low Kb/low Db" phenotype is nonmetastatic as is a "high Kb/high Db" phenotype; a "low Kb/high Db" is highly metastatic and a "medium Kb/high Db" is moderately metastatic. We find support for this notion of imbalance in experiments on MHC modulation by interferon and retinoic acid. Interferon increases both Kb and Db expression of A9 and D122 clones yet the net increase of Db was greater than Kb. This was associated with an increase in metastasis formation. Retinoic acid increases the expression of the Db gene product on the nonmetastatic A9, clone, without apparent changes in Kb expression. This treatment shifts the A9 to a high-metastatic phenotype. The significance of this imbalance to the tumor--host relationship is discussed.

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 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 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.