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
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.