Numerous papers in recent years have illustrated the importance of extracellular matrix remodeling for normal development. These remodeling events are carried out by matrix metalloproteases (MMPs) such as MMP-2 and MMP-9. The membrane-bound MT1-MMP appears to play a central role in the processing and activation of MMPs. One of the processes during embryogenesis that is dependent on the action of matrix metalloproteases is angiogenesis. Just as metalloproteases are required for growing tissues to establish vascular networks, the same proteases are needed when tumors establish a vasculature. Oh et al., in an elegant paper, identify RECK as a central regulator of matrix remodeling [1xThe membrane-anchored MMP inhibitor RECK is a key regulator of extracellular matrix integrity and angiogenesis. Oh, J. et al. Cell. 2001; 107: 789–800Abstract | Full Text | Full Text PDF | PubMed | Scopus (440)See all References[1]. RECK is a GPI-anchored membrane protein with serine protease inhibitor activity, previously identified in an expression cloning strategy, which the authors have gone on to study by using gene targeting and tumor transplantation in mice.Inactivation of the RECK gene in mice leads to embryonic death at day 10.5. Analysis of the embryos reveals a smaller size, disarray of mesenchymal tissues and hemorrhage. Closer examination of blood vessels demonstrated defects in blood vessel maturation. In vitro studies of RECK function reveal that it inhibits the activity of MT1-MMP, thus indirectly also inhibiting other MMPs such as MMP-2 and MMP-9. Studies of cells from the RECK-deficient embryos intercrossed with MMP-2-deficient embryos support this mechanism of action as the lack of MMP-2 partly rescued the RECK phenotype. To analyze the importance of RECK for tumor angiogenesis, the fibrosarcoma cell line HT1080, with or without RECK, was transplanted into nude mice. The tumors derived from cells overexpressing RECK show reduced tumor vasculature sprouting, resulting in massive tumor death.The paper by Oh et al. thus indicates that tightly regulated matrix turnover is needed for embryonic development and tumor angiogenesis. When an inhibitor of a central MMP activator is lacking, too much ECM is degraded, leading to dysregulated development. However, when too much of the MMP inhibitor RECK is expressed in tumor cells, vessel sprouting cannot occur. These very interesting results shed light on the molecular mechanism of RECK, which thus appears to be a central regulator of MMPs and angiogenesis. The authors’ findings warrant a fresh look at novel therapeutic strategies in tumor biology, and we will surely hear more about RECK in the years to come.