Cytokine-regulated urokinase-type-plasminogen-activator (uPA) production by human breast fibroblasts in vitro

Citation
Am. Sieuwerts et al., Cytokine-regulated urokinase-type-plasminogen-activator (uPA) production by human breast fibroblasts in vitro, BREAST CANC, 55(1), 1999, pp. 9-20
Citations number
43
Categorie Soggetti
Oncology,"Onconogenesis & Cancer Research
Journal title
BREAST CANCER RESEARCH AND TREATMENT
ISSN journal
01676806 → ACNP
Volume
55
Issue
1
Year of publication
1999
Pages
9 - 20
Database
ISI
SICI code
0167-6806(199905)55:1<9:CU(PB>2.0.ZU;2-M
Abstract
It has been shown that, in breast stroma, urokinase-type plasminogen activa tor (uPA) mRNA is predominantly expressed by myofibroblasts located at the invasive areas of the tumor. To examine which factors present in a tumor en vironment are candidates responsible for the induction of these uPA-produci ng myofibroblasts, we studied in vitro the capacity of a paired panel of no rmal and tumor-derived human breast fibroblasts to produce uPA protein and the myofibroblast marker alpha-smooth-muscle-actin (alpha-SMA) in response to various cytokines implicated in the process of tissue-remodeling during malignant transformation. We found that fibroblasts produced increased amounts of uPA protein after e xposure to a-FGF, b-FGF, EGF, PDGF-BB, and IFN-gamma, were unaffected in th is respect by IL-6, M-CSF, GM-CSF and Oncostatin M, and produced decreased amounts of uPA protein after exposure to IL-1 alpha, TNF-alpha, IGF-I, and IGF-II. None of these cytokines were able to induce a striking increase in the fraction of alpha-SMA-positive fibroblasts. On the other hand, 25 pM TG F beta(1) increased the fraction of alpha-SMA-positive fibroblasts 5-fold i n both normal and tumor-tissue-derived fibroblasts. Nonetheless, the normal -derived fibroblasts were unaffected in their uPA-producing capacity by TGF beta(1), and the tumor-derived fibroblasts produced decreased amounts of u PA protein after exposure to this cytokine, implying that at least in vitro the myofibroblast phenotype is not a prerequisite for the production of uP A by human breast fibroblasts. In addition, we established that the basal-u PA-production of both normal and tumor-derived fibroblasts was increased by autocrinely produced b-FGF-like activity, and that the basal-uPA-productio n of at least the normal-derived fibroblasts was decreased by autocrinely p roduced IGF-like activity. Altogether, our data suggest an active role for fibroblasts in the process of uPA-directed breast tumor proteolysis.