title: Bone marrow-derived myofibroblasts are the providers of pro-invasive matrix metalloproteinase 13 in primary tumor.
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.
authors.affiliation: Laboratory of Tumor and Development Biology, GIGA-Cancer, University of Liège, Liège, Belgium.
authors.forename: Julie
authors.initials: J
authors.lastname: Lecomte
authors.forename: Anne
authors.initials: A
authors.lastname: Masset
authors.forename: Silvia
authors.initials: S
authors.lastname: Blacher
authors.forename: Ludovic
authors.initials: L
authors.lastname: Maertens
authors.forename: André
authors.initials: A
authors.lastname: Gothot
authors.forename: Marie
authors.initials: M
authors.lastname: Delgaudine
authors.forename: Françoise
authors.initials: F
authors.lastname: Bruyère
authors.forename: Oriane
authors.initials: O
authors.lastname: Carnet
authors.forename: Jenny
authors.initials: J
authors.lastname: Paupert
authors.forename: Martin
authors.initials: M
authors.lastname: Illemann
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Foidart
authors.forename: Ida K
authors.initials: IK
authors.lastname: Lund
authors.forename: Gunilla
authors.initials: G
authors.lastname: Høyer-Hansen
authors.forename: Agnes
authors.initials: A
authors.lastname: Noel
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology*; D005434:Flow Cytometry; D006801:Humans; D007124:Immunoenzyme Techniques; D017403:In Situ Hybridization; D053509:Matrix Metalloproteinase 13 / Q000502:physiology*; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058628:Myofibroblasts / Q000378:metabolism / Q000473:pathology*; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment
chemical_list: D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D053509:Matrix Metalloproteinase 13; C507081:Mmp13 protein, mouse