Poorly liver metastatic large-cell lymphoma RAWll7.P cells were sequentially selected in vitro for increased adhesion to murine hepatic sinusoidai endothelial cells. After three or four sequential selections, the selected sublines showed increased rates of adhesion to target hepatic microvessel endothelial cells and increased formation of experimental metastases in the liver. However, the endothelial cell adhesion-selected RAW117 sublines were generally unstable and gradually lost their enhanced adhesive and metastatic properties during passage in culture. Highly metastatic, liver-selected RAWll7-H10 large-cell lymphoma cells were more resistant to the cytostatic effects of interferon-7 (IFN-7) than poorly metastatic unselected parental RAW117-P cells. When tested for their sensitivity to IFN-7, the endothelial cell adhesion variants were significantly more resistant than the unselected RAW117.P cells, but after a 72-h treatment with IFN.y, the in vitro-selected calls lost their enhanced endothelial cell adhesion characteristics, their potential to colonize the liver, and their ability to grow when injected at subcutaneous or intramuscular sites. In contrast, the metastatic potential of similarly treated RAWll7-P cells was unaffected by IFN-~, during a 72-h treatment. Sequential selection of RAWll7-P cells for increased resistance to IFN-y in vitro resulted in variant lines that were refractory to the growth-inhibiting effects of IFN-7, and these IFN-7-selected variants were also less adhesive to liver microvessel endothelial cells. The IFN-7-selected variants also lost their experimental metastatic potentials completely and their tumorigenicities at sites of subcutaneous or intramuscular injection. Cytofluorographic analysis indicated reduced cell surface expression of H-2K d antigen and fibronectin receptor on the selected variant cells but no change in cell surface /~ heavy chain immunoglobulin. The unselected and selected RAW117 lines had similar sensitivities to natural killer (NK) cell-mediated cytolysis, indicating that the in vlvo differences were probably not due to differences in NK cell-mediated cytolysis. The results suggest that selection for adhesion to organ microvessel endothelial cells or sequential exposure to certain cytokines can affect the adhesive, growth and metastatic properties of RAW117 cells without modifying their responses to NK cells.