title: Recruitment of Matrix Metalloproteinase-9 (MMP-9) to the Fibroblast Cell Surface by Lysyl Hydroxylase 3 (LH3) Triggers Transforming Growth Factor-β (TGF-β) Activation and Fibroblast Differentiation.
abstract: Solid tumor growth triggers a wound healing response. Similar to wound healing, fibroblasts in the tumor stroma differentiate into myofibroblasts (also referred to as cancer-associated fibroblasts) primarily, but not exclusively, in response to transforming growth factor-β (TGF-β). Myofibroblasts in turn enhance tumor progression by remodeling the stroma. Among proteases implicated in stroma remodeling, matrix metalloproteinases (MMPs), including MMP-9, play a prominent role. Recent evidence indicates that MMP-9 recruitment to the tumor cell surface enhances tumor growth and invasion. In the present work, we addressed the potential relevance of MMP-9 recruitment to and activity at the surface of fibroblasts. We show that recruitment of MMP-9 to the fibroblast cell surface occurs through its fibronectin-like (FN) domain and that the molecule responsible for the recruitment is lysyl hydroxylase 3 (LH3). Functional assays suggest that both pro- and active MMP-9 trigger α-smooth muscle actin expression in cultured fibroblasts, reflecting myofibroblast differentiation, possibly as a result of TGF-β activation. Moreover, the recombinant FN domain inhibited both MMP-9-induced TGF-β activation and α-smooth muscle actin expression by displacing MMP-9 from the fibroblast cell surface. Together our results uncover LH3 as a new docking receptor of MMP-9 on the fibroblast cell surface and demonstrate that the MMP-9 FN domain is essential for the interaction. They also show that the recombinant FN domain inhibits MMP-9-induced TGF-β activation and fibroblast differentiation, providing a potentially attractive therapeutic reagent toward attenuating tumor progression where MMP-9 activity is strongly implicated.
authors.affiliation: From the Division of Experimental Pathology, Institute of Pathology, CHUV, Faculty of Biology and Medicine, University of Lausanne, Rue du Bugnon 25, Lausanne CH1011, Switzerland.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Dayer
authors.affiliation: From the Division of Experimental Pathology, Institute of Pathology, CHUV, Faculty of Biology and Medicine, University of Lausanne, Rue du Bugnon 25, Lausanne CH1011, Switzerland Ivan.Stamenkovic@chuv.ch.
authors.forename: Ivan
authors.initials: I
authors.lastname: Stamenkovic
mesh_terms: D000818:Animals; D016466:CHO Cells; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002469:Cell Separation; D006224:Cricetinae; D003412:Cricetulus; D005347:Fibroblasts / Q000378:metabolism*; D005434:Flow Cytometry; D057809:HEK293 Cells; D006801:Humans; D008099:Liver / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D058628:Myofibroblasts / Q000166:cytology; D008240:Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D059016:Tumor Microenvironment
chemical_list: D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; C475767:PLOD3 protein, human; D008240:Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9
keywords: fibroblast; matrix metalloproteinase (MMP); myofibroblast; transforming growth factor β (TGF-B); tumor microenvironment
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