In Vivo Evidence That the Stromelysin-3 Metalloproteinase Contributes in a Paracrine Manner to Epithelial Cell Malignancy |
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Authors: | Rgis Masson Olivier Lefebvre Agns Noël Mostapha El Fahime Marie-Pierre Chenard Corinne Wendling Florence Kebers Marianne LeMeur Andre Dierich Jean-Michel Foidart Paul Basset and Marie-Christine Rio |
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Institution: | Régis Masson, Olivier Lefebvre, Agnès Noël, Mostapha El Fahime, Marie-Pierre Chenard, Corinne Wendling, Florence Kebers, Marianne LeMeur, Andrée Dierich, Jean-Michel Foidart, Paul Basset, and Marie-Christine Rio |
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Abstract: | Stromelysin-3 (ST3; Basset, P., J.P. Bellocq, C. Wolf, I. Stoll, P. Hutin, J.M. Limacher, O.L. Podhajcer, M.P. Chenard, M.C. Rio, P. Chambon. 1990. Nature. 348:699–704) is a matrix metalloproteinase (MMP) expressed in mesenchymal cells located close to epithelial cells, during physiological and pathological tissue remodeling processes. In human carcinomas, high ST3 levels are associated with a poor clinical outcome, suggesting that ST3 plays a role during malignant processes. In this study we report the ST3 gene inactivation by homologous recombination. Although ST3 null mice (ST3−/−) were fertile and did not exhibit obvious alterations in appearance and behavior, the lack of ST3 altered malignant processes. Thus, the suppression of ST3 results in a decreased 7,12-dimethylbenzanthracene-induced tumorigenesis in ST3−/− mice. Moreover, ST3−/− fibroblasts have lost the capacity to promote implantation of MCF7 human malignant epithelial cells in nude mice (P < 0.008). Finally, we show that this ST3 paracrine function requires extracellular matrix (ECM)-associated growth factors. Altogether, these findings give evidence that ST3 promotes, in a paracrine manner, homing of malignant epithelial cells, a key process for both primary tumors and metastases. Therefore, ST3 represents an appropriate target for specific MMP inhibitor(s) in future therapeutical approaches directed against the stromal compartment of human carcinomas. |
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Keywords: | myosin actin cytoskeleton membranes Golgi complex |
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