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Catalytically Inactive Human Cathepsin D Triggers Fibroblast Invasive Growth

V. Laurent-Matha, Sharon Maruani-Herrmann, C. Prébois, M. Beaujouin, M. Glondu, A. Noël, Marie Luz Alvarez-Gonzalez, S. Blacher, Peter Coopman, Stephen Baghdiguian, C. Gilles, Jadranka Lončarek, G. Freiss, F. Vignon, E. Liaudet-Coopman
Published 2005 · Biology, Medicine

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The aspartyl-protease cathepsin D (cath-D) is overexpressed and hypersecreted by epithelial breast cancer cells and stimulates their proliferation. As tumor epithelial–fibroblast cell interactions are important events in cancer progression, we investigated whether cath-D overexpression affects also fibroblast behavior. We demonstrate a requirement of cath-D for fibroblast invasive growth using a three-dimensional (3D) coculture assay with cancer cells secreting or not pro-cath-D. Ectopic expression of cath-D in cath-D–deficient fibroblasts stimulates 3D outgrowth that is associated with a significant increase in fibroblast proliferation, survival, motility, and invasive capacity, accompanied by activation of the ras–MAPK pathway. Interestingly, all these stimulatory effects on fibroblasts are independent of cath-D proteolytic activity. Finally, we show that pro-cath-D secreted by cancer cells is captured by fibroblasts and partially mimics effects of transfected cath-D. We conclude that cath-D is crucial for fibroblast invasive outgrowth and could act as a key paracrine communicator between cancer and stromal cells, independently of its catalytic activity.
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