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High Cancer Cell Death in Syngeneic Tumors Developed in Host Mice Deficient for the Stromelysin-3 Matrix Metalloproteinase¹

Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique/Institut National de la Santé et de la Recherche Médicale U184/ULP BP 163, 67404 Illkirch Cedex, Communauté Urbaine de Strasbourg [A. B., R. M., M. E. F., P. B., M-C. R.]; Service d’Anatomie Pathologique Générale, Centre Hospitalier Universitaire de Hautepierre, 67098 Strasbourg Cedex [M-P. C., J-P. B.]; and Institut Curie, Institut National de la Santé et de la Recherche Médicale U255, 75248 Paris Cedex 05 [L. C., C. S-F.], France

Matrix metalloproteinases (MMPs) are extracellular enzymes. Some of them are known to be involved in tumor development and/or progression. Several cellular functions have been proposed for MMPs during malignant processes. Notably, they may be involved in tissue-remodeling processes through their ability to digest matrix components or to participate in tumor neoangiogenesis and, subsequently, in cancer cell proliferation. One of these MMPs, stromelysin-3 (ST3/MMP11), although devoid of enzymatic activity against the matrix components, is associated with human tumor progression and poor patient clinical outcome. Using several in vivo experimental models, it has been demonstrated that ST3 expression by the fibroblastic cells surrounding malignant epithelial cells promotes tumorigenesis in a paracrine manner. The present study was devoted to the identification of the cellular function underlying this ST3-induced tumor promotion using a syngeneic tumorigenesis model in mice. Our results show that ST3 exhibits a new and unexpected role for a MMP, because ST3-increased tumorigenesis does not result from increased neoangiogenesis or cancer cell proliferation but from decreased cancer cell death through apoptosis and necrosis. Thus, during malignancy, the cellular function of ST3 is to favor cancer cell survival in the stromal environment.

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