Bone marrow-derived myofibroblasts are the providers of pro-invasive matrix metalloproteinase 13 in primary tumor

Julie Lecomte, Anne Masset, Silvia Blacher, Ludovic Maertens, André Gothot, Marie Delgaudine, Françoise Bruyère, Oriane Carnet, Jenny Paupert, Martin Illemann, Jean-Michel Foidart, Ida K Lund, Gunilla Høyer-Hansen, Agnes Noel

    32 Citationer (Scopus)

    Abstract

    Carcinoma-associated fibroblasts are key contributors of the tumor microenvironment that regulates carcinoma progression. They consist of a heterogeneous cell population with diverse origins, phenotypes, and functions. In the present report, we have explored the contribution of bone marrow (BM)-derived cells to generate different fibroblast subsets that putatively produce the matrix metalloproteinase 13 (MMP13) and affect cancer cell invasion. A murine model of skin carcinoma was applied to mice, irradiated, and engrafted with BM isolated from green fluorescent protein (GFP) transgenic mice. We provide evidence that one third of BM-derived GFP(+) cells infiltrating the tumor expressed the chondroitin sulfate proteoglycan NG2 (pericytic marker) or α-smooth muscle actin (α-SMA, myofibroblast marker), whereas almost 90% of Thy1(+) fibroblasts were originating from resident GFP-negative cells. MMP13producing cells were exclusively α-SMA(+) cells and derived from GFP(+) BM cells. To investigate their impact on tumor invasion, we isolated mesenchymal stem cells (MSCs) from the BM of wild-type and MMP13-deficient mice. Wild-type MSC promoted cancer cell invasion in a spheroid assay, whereas MSCs obtained from MMP13-deficient mice failed to. Our data support the concept of fibroblast subset specialization with BM-derived α-SMA(+) cells being the main source of MMP13, a stromal mediator of cancer cell invasion.
    OriginalsprogEngelsk
    TidsskriftNeoplasia
    Vol/bind14
    Udgave nummer10
    Sider (fra-til)943-51
    Antal sider9
    ISSN1522-8002
    DOI
    StatusUdgivet - 2012

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