Urokinase-type-plasminogen-activator(UPA) production by human breast (myo)fibroblastsin vitro: Influence of transforming growth factor-β1 (TGFβ1) compared with factor(s) released by human epithelial-carcinoma cells

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Abstract
The urokinase‐type plasminogen activator (uPA) may be considered as a key enzyme in the processes of cancer cell invasion and metastasis. Evidence has been presented that, in breast stroma, uPA is expressed predominantly by myofibroblasts located at the invasive areas of the tumor. To examine whether transforming growth factor type‐1 (TGFβ1) produced by breast‐carcinoma cells is a candidate responsible for the induction of uPA‐producing myofibroblasts, we studied in vitro the capacity of normal and tumor‐derived human breast fibroblasts to express uPA and the myofibroblast marker α‐smooth‐muscle actin in response to TGFβ1. Next, we compared these influences with those elicited by factor(s) released by epithelial‐cancer cells. In all 8 fibroblast strains tested, TGFβ1 induced a similar concentration‐dependent increase in the fraction of α‐smooth‐muscle‐actin‐positive fibroblasts. While uPA expression was decreased by TGFβ1 in most of the fibroblast strains, 2 strains were relatively insensitive to TGFβ1 in this respect. Although factors present in media conditioned by non‐uPA‐producing epithelial‐tumor cells could trigger fibroblasts to become potent producers of uPA, the TGFβ1 content of the conditioned media were linked to the differential effects of externally added TGFβ1 with respect to uPA expression. The data demonstrate that, although fibroblasts may utilize TGFβ1 secreted by tumor cells to differentiate into myofibroblasts, tumor cells secrete factor(s) other than TGFβ1 ultimately responsible for the generation of powerful uPA‐producing fibroblasts. Int. J. Cancer 76:829–835, 1998.