Progression toward metastatic phenotype with loss of growth-inhibiting tumor-cell/cell interactions in vivo.

Five autonomous sublines, T4-O1320, T4-O1320CY, T4-O1165, T4-O1145 and T4-O196, were established from the transplantable hormone-dependent mouse mammary tumor, TPDMT-4, by passaging under different conditions. These autonomous tumors were characterized by rapid growth in DDD virgin mice and the parental TPDMT-4 by no growth in these mice. Thus, 10(5) T4-O1320, 2 x 10(4) T4-O1320CY, 2 x 10(3) T4-O1165, 2 x 10(3) T4-O1145 and 10(3) T4-O196 cells were co-injected with 5 x 10(5) TPDMT-4 cells into virgin mice to determine whether or not hormone-dependent tumor cells influence the growth of autonomous tumor cells. TPDMT-4 cells retarded the growth of T4-O1320 and T4-O1320CY tumors but accelerated that of T4-O1165, T4-O1145 and T4-O196. Irradiated TPDMT-4 cells stimulated the growth of all the sublines except T4-O1320. In 3-dimensional collagen-gel culture, T4-O1320 and T4-O1320CY cells formed branched or stellate structures similar to normal mammary glands, as did TPDMT-4, but T4-O1165, T4-O1145 and T4-O196 cells grew as rounded masses with knobs and showed a completely different morphology. T4-O1165, T4-O1145 and T4-O196 cells, but not the others, had lung-colonizing ability. Chromosomal aberration was found in T4-O1320CY and T4-O196 but not in the others. Thus, the susceptibility of autonomous subline tumor cells to growth-inhibitory regulation from the parental hormone-dependent tumor cells correlated well with growth morphology within collagen gels and metastatic ability, but not with chromosomal aberration. The results suggest that metastatically-competent tumor-cell variants, once they appear, may have a growth advantage in hormone-dependent mammary tumors.