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Earlier Onset of Tumoral Angiogenesis in Matrix Metalloproteinase-19–Deficient Mice

¹ Laboratory of Tumor and Developmental Biology, Center for Experimental Cancer Research, Center for Biomedical Integrative Genoproteomics, University of Liège, Tour de Pathologie (B23); ² Department of Gynecology, Centre Hospitalier Universitaire, Liège, Belgium; ³ Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, Oviedo, Spain; and ⁴ Centro Investigacion Cancer, Salamanca, Spain

Requests for reprints: Agnès Noël, Laboratory of Tumor and Developmental Biology, University of Liège, Tour de Pathologie (B23), Sart-Tilman, B-4000 Liège, Belgium. Phone: 32-4-366-25-69; Fax: 32-4-366-29-36; E-mail: agnes.noel{at}ulg.ac.be.

Among matrix metalloproteinases (MMP), MMP-19 displays unique structural features and tissue distribution. In contrast to most MMPs, MMP-19 is expressed in normal human epidermis and down-regulated during malignant transformation and dedifferentiation. The contribution of MMP-19 during tumor angiogenesis is presently unknown. In an attempt to give new insights into MMP-19 in vivo functions, angiogenic response of mutant mice lacking MMP-19 was analyzed after transplantation of murine malignant PDVA keratinocytes and after injection of Matrigel supplemented with basic fibroblast growth factor. In situ hybridization and immunohistochemical analysis revealed that MMP-19 is produced by host mesenchymal cells but not by endothelial capillary cells or CD11b-positive inflammatory cells. Based on a new computer-assisted method of quantification, we provide evidence that host MMP-19 deficiency was associated with an increased early angiogenic response. In addition, increased tumor invasion was observed in MMP-19–/– mice. We conclude that, in contrast to most MMPs that promote tumor progression, MMP-19 is a negative regulator of early steps of tumor angiogenesis and invasion. These data highlight the requirement to understand the individual functions of each MMP to improve anticancer strategies. (Cancer Res 2006; 66(10): 5234-41)

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