Quantitative relationships of intravascular tumor cells, tumor vessels, and pulmonary metastases following tumor implantation.

Summary An experimental model has been developed to quantify some of the major processes initiated by tumor transplantation and culminating in pulmonary metastases. The T241 fibrosarcoma, chosen because of its high hematogenous metastatic propensity and reproducible biological behavior, is transplanted into the femoral region of the C57BL mouse. Experiments are performed at specified times after transplantation to determine the dynamics of tumor growth, density, and size distribution of perfused tumor vessels, entry rate of tumor cells into the circulation, and the number of pulmonary metastases. Estimates of the entry rate of tumor cells into the circulation are obtained by perfusing tumors with an oxygenated, cell-free medium to allow the counting of single tumor cells and tumor cell clumps collected in the venous effluent. The tumor vascular network appears at approximately Day 4, while tumor cells are first observed in the perfusate approximately 5 days after transplantation. The concentration of effluent tumor cells, singly and in clumps, increases rapidly until Day 10, after which the rate of cell entry into the perfusion is diminished. A linear relation is found between the density of perfused vessels and the concentration of effluent tumor cells. Metastases, first observed on Day 10, increase rapidly with time, at a rate similar to that of the concentration of effluent tumor cell clumps containing 4 or more cells. These studies suggest that dynamics of hematogenously initiated metastases depend strongly on the entry rate of tumor cell clumps into the circulation, which in turn is intimately linked to tumor vascularization.