Study of Tumor Progression in vivo and in vitro using

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Five autonomous sublines, T4-OI320 (329), T4-OI320CY (320CY), T4-OI165 (165), T4-OI145 (145), and T4-OI96 (96), were established from the transpalantable hormone-dependent mouse mammary tumor, TPDMT-4 (T4), by passaging under different conditions. These autonomous tumors were characterized by rapid growth in DDD virgin mice and the parental T4 by no growth in them. Thus, 10^5320,210^4320CY,2*10^3165,2*10^3145 and 10^396 cells were co-injected with 5*10^5T4 cells into virgin mice to determine whether hormone-dependent tumor cells influence the growth of autonomous tumor cells or not. T4 cells retarded the growth of 320 and 320CY tumors but accelerated that of 165,145 and 96. Irradiated T4 cells stimulated the growth of all the sublines but 320. In three-dimensional collagen gel culture, 320 and 320CY cells formed branched or stellate structures similar to normal mammary glands as did T4, but 165,145 and 96 cells grew as rounded masses with knobs and showed completely different morphology. 165,145 and 96 cells but not the others had lung-colonizing capability. In the collagen gel culture system, an antibiotic protease inhibitor exerted a stronger growth-inhibiting effect on the metastatic than on the parent and non-metastatic tumors. Thus, the susceptibility of autonomous subline tumor cells to the growth-inhibitory regulation from the parenetal hormone-dependent tumor cells was well correlated with growth morphology within collagen gels and metastatic property. The results suggest that metastatically-competent tumor cell variants, once they appear, may have a growth advantage in hormone-dependent mammary tumors. Application of this in vitro sytem to human breast cancer is in progress.