INTERLEUKIN-6 AND 12-O-TETRADECANOYL PHORBOL-13-ACETATE ACT SYNERGISTICALLY IN INDUCING CELL-CELL SEPARATION AND MIGRATION OF HUMAN BREAST-CARCINOMA CELLS

Interleukin-6 (IL-6) causes an epithelial to fibroblastoid conversion and an increase in the motility of human ductal breast carcinoma cell lines ZR-75-1 and T-47D. Although IL-6 decreases DNA synthetic activity in these cell lines, the IL-6-induced alterations in cell shape and motility occur independently of inhibition of DNA synthesis per se. Whereas tumor necrosis factor α (TNF-α) inhibits DNA synthesis in T-471) cells, it does not cause an epithelial-fibroblastoid conversion or other major morphological changes and does not increase cell motility; TNF-α rapidly lyses a majority of ZR-75-1 cells. Furthermore, the DNA synthesis inhibitors 5-fluoro-2′-deoxyuridine (FUDR) and methotrexate (MTX) also do not cause effects mimicking the action of IL-6 on cell structure and motility. Transforming growth factors α and β1, acidic and basic fibroblast growth factors, epidermal growth factor, and insulin-like growth factor-1 (TGF-α, TGF-β1, aFGF, bFGF, EGF, and IGF-1) have little or no effect on breast cancer cell morphology, which serves to exclude the possibility that the IL-6-induced changes are a consequence of induction of these growth factors by IL-6. 12-O-tetradecanoyl phorbol-13-acetate (TPA) but not 8-bromoadenosine 3′,5′-cyclic monophosphate (Br-cAMP) induces changes in the morphology and associative behavior of ZR-75-1 cells that are similar but not identical to those caused by IL-6. The TPA-induced alterations are not blocked by anti-IL-6 neutralizing antibodies; staurosporine inhibits the TPA-induced cell alterations but not those induced by IL-6. IL-6 and TPA used together have a phenotypic effect that greatly exceeds that of either agent alone and results in extensive cell scattering in less than 1 day. These findings are consistent with the hypothesis that IL-6 and TPA induce similar morphological changes and cell scattering via independent pathways. © 1991.