SCATTER FACTOR MODULATES THE METASTATIC PHENOTYPE OF THE EMT6 MOUSE MAMMARY-TUMOR

EMT6 is a transplantable mouse mammary tumor cell line that has been u tilized widely as a model system to study the effects of various treat ments on local tumor growth and pulmonary metastasis. In this study, w e examined the cellular mechanisms by which scatter factor (SF), a fib roblast-derived cytokine that stimulates epithelial cell motility, may contribute to tumor-cell dissemination, using the EMT6 model system. In vitro, SF stimulated EMT6 cell motility, invasiveness and cell-surf ace expression of urokinase (an enzyme required for cell migration thr ough tissue). SF differentially stimulated EMT6 cell adhesion to and m igration onto surfaces coated with collage I and laminin. EMT6 cells t reated in vitro with SF and injected i.v. into isogeneic BALB/c-Rw mic e showed a small but significant increase (1.7-fold) in lung colony fo rmation as compared with control cells. For EMT6 cells in vitro, SF ha d no effect on DNA synthesis, cell proliferation, cell size distributi on, or in vitro colony-forming ability. Thus, the increase in lung col onization may be due to enhanced ability of SF-treated cells to adhere to subendothelial basement membrane or to invade through tissue. Stud ies of the tissue distribution of SF in BALB/c-Rw mice demonstrated hi gh levels of active factor in the lung. Thus, the presence of endogeno us pulmonary SF may have reduced the degree to which SF treatment stim ulated EMT6 lung colonization. Significant SF activity was also found in extracts of EMT6 tumors. Cultured EMT6 cells did not produce SF, bu t did produce high titers of a soluble low-molecular-weight protein ac tivity that is capable of stimulating SF production in human fibroblas ts 3- to 5-fold. EMT6 tumor extracts contained high titers of a simila r SF-inducing activity. These observations suggest that SF may contrib ute to the invasive and metastatic phenotype of EMT6 cells via a parac rine mechanism in which tumor cells induce the production of SF in str omal fibroblasts. (C) 1994 Wiley-Liss, Inc.