UROKINASE-TYPE-PLASMINOGEN-ACTIVATOR (UPA) PRODUCTION BY HUMAN BREAST(MYO)FIBROBLASTS IN-VITRO - INFLUENCE OF TRANSFORMING GROWTH FACTOR-BETA(1) (TGF-BETA(1)) COMPARED WITH FACTOR(S) RELEASED BY HUMAN EPITHELIAL-CARCINOMA CELLS

The urokinase-type plasminogen activator (uPA) may be considered as a key enzyme in the processes of cancer cell invasion and metastasis. Ev idence has been presented that, in breast stroma, uPA is expressed pre dominantly by myofibroblasts located at the invasive areas of the tumo r. To examine whether transforming growth factor type-1 (TGF beta(1)) produced by breast-carcinoma cells is a candidate responsible for the induction of uPA-producing myofibroblasts, we studied in vitro the cap acity of normal and tumor-derived human breast fibroblasts to express uPA and the myofibroblast marker alpha-smooth-muscle actin in response to TGF beta(1). Next, we compared these influences with those elicite d by factor(s) released by epithelial-cancer cells. In all 8 fibroblas t strains tested, TGF beta(1) induced a similar concentration-dependen t increase in the fraction of alpha-smooth-muscle-actin-positive fibro brasts. While uPA expression was decreased by TGF beta(1) in most of t he fibroblast strains, 2 strains were relatively insensitive to TGF be ta(1) in this respect. Although factors present in media conditioned b y non-uPA-producing epithelial-tumor cells could trigger fibroblasts t o become potent producers of uPA, the TGF beta(1) content of the condi tioned media were linked to the differential effects of externally add ed TGF beta(1) with respect to uPA expression. The data demonstrate th at, although fibroblasts may utilize TGF beta(1) secreted by tumor cel ls to differentiate into myofibroblasts, tumor cells secrete factor(s) other than TGF beta(1) ultimately responsible for the generation of p owerful uPA-producing fibroblasts. (C) 1998 Wiley-Liss, Inc.