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

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Abstract

It has been shown that, in breast stroma, urokinase‐type plasminogen activator (uPA) mRNA is predominantly expressed by myofibroblasts located at the invasive areas of the tumor. To examine which factors present in a tumor environment are candidates responsible for the induction of these uPA‐producing myofibroblasts, we studied in vitro the capacity of a paired panel of normal and tumor‐derived human breast fibroblasts to produce uPA protein and the myofibroblast marker α‐smooth‐muscle‐actin (α‐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 exposure to a‐FGF, b‐FGF, EGF, PDGF‐BB, and IFN‐γ, were unaffected in this respect by IL‐6, M‐CSF, GM‐CSF and Oncostatin M, and produced decreased amounts of uPA protein after exposure to IL‐1α, TNF‐α, IGF‐I, and IGF‐II. None of these cytokines were able to induce a striking increase in the fraction of α‐SMA‐positive fibroblasts. On the other hand, 25 pM TGFβ1 increased the fraction of α‐SMA‐positive fibroblasts 5‐fold in both normal and tumor‐tissue‐derived fibroblasts. Nonetheless, the normal‐derived fibroblasts were unaffected in their uPA‐producing capacity by TGFβ1, and the tumor‐derived fibroblasts produced decreased amounts of uPA protein after exposure to this cytokine, implying that at least in vitro the myofibroblast phenotype is not a prerequisite for the production of uPA by human breast fibroblasts. In addition, we established that the basal‐uPA‐production of both normal and tumor‐derived fibroblasts was increased by autocrinely produced b‐FGF‐like activity, and that the basal‐uPA‐production of at least the normal‐derived fibroblasts was decreased by autocrinely produced IGF‐like activity.

Altogether, our data suggest an active role for fibroblasts in the process of uPA‐directed breast tumor proteolysis.

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Authors and Affiliations

  1. Department of Medical Oncology (Division of Endocrine Oncology), Rotterdam Cancer Institute (Daniel den Hoed Kliniek)/Academic Hospital Rotterdam, Rotterdam, The Netherlands

    Anieta M. Sieuwerts, Jan G.M. Klijn & John A. Foekens

  2. Department of Pathology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek)/Academic Hospital Rotterdam, Rotterdam, The Netherlands

    Sonja C. Henzen‐Logmans

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  1. Anieta M. Sieuwerts
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  3. Sonja C. Henzen‐Logmans
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Sieuwerts, A.M., Klijn, J.G., Henzen‐Logmans, S.C. et al. Cytokine‐regulated urokinase‐type‐plasminogen‐activator (uPA) production by human breast fibroblasts in vitro. Breast Cancer Res Treat 55, 9–20 (1999). https://doi.org/10.1023/A:1006190729866

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