Ingvarsen, Signe7; Porse, Astrid5; Erpicum, Charlotte5; Maertens, Ludovic5; Jürgensen, Henrik J5; Madsen, Daniel H7; Melander, Maria C5; Gårdsvoll, Henrik7; Høyer-Hansen, Gunilla8; Noel, Agnès5; Holmbeck, Kenn5; Engelholm, Lars H9; Behrendt, Niels7
1 Biomolecular Sciences, Department of Biology, Faculty of Science, Københavns Universitet2 Høyer-Hansen Group, BRIC Research Groups, BRIC, Københavns Universitet3 Engelholm Group, BRIC Research Groups, BRIC, Københavns Universitet4 Behrendt Group, BRIC Research Groups, BRIC, Københavns Universitet5 unknown6 Department of Clinical Medicine, Faculty of Health and Medical Sciences, Københavns Universitet7 Behrendt Group, BRIC Research Groups, BRIC, Københavns Universitet8 Department of Clinical Medicine, Faculty of Health and Medical Sciences, Københavns Universitet9 Engelholm Group, BRIC Research Groups, BRIC, Københavns Universitet
impact on lymphangiogenesis
The group of matrix metalloproteases (MMPs) is responsible for multiple processes of extracellular matrix remodeling in the healthy body but also for matrix and tissue destruction during cancer invasion and metastasis. The understanding of the contributions from each individual MMP, both in healthy and pathological events, has been complicated by the lack of specific inhibitors and the fact that some of the potent MMPs are multifunctional enzymes. These factors have also hampered the setup of therapeutic strategies targeting MMP activity. A tempting target is the membrane-associated MT1-MMP, which has well-documented importance in matrix degradation but which takes part in more than one pathway in this regard. In this report, we describe the selective targeting of a single function of this enzyme by means of a specific monoclonal antibody against MT1-MMP, raised in an MT1-MMP knock-out mouse. The antibody blocks the enzyme ability to activate proMMP-2 without interfering with the collagenolytic function or the general proteolytic activity of MT1-MMP. Using this antibody, we have shown that the MT1-MMP-catalyzed activation of proMMP-2 is involved in the outgrowth of cultured lymphatic endothelial cells in a collagen matrix in vitro, as well as in lymphatic vessel sprouting assayed ex vivo. This is the first example of the complete inactivation of a single function of a multifunctional MMP and the use of this strategy to pursue its role.
Journal of Biological Chemistry, 2013, Vol 288, Issue 15, p. 10195-204