Catalytically Inactive Human Cathepsin D Triggers Fibroblast Invasive Growth

• Published in: The Journal of cell biology Vol. 168; no. 3; pp. 489 - 499
• Main Authors: Laurent-Matha, Valérie, Maruani-Herrmann, Sharon, Prébois, Christine, Beaujouin, Mélanie, Glondu, Murielle, Noël, Agnès, Alvarez-Gonzalez, Marie Luz, Blacher, Sylvia, Coopman, Peter, Baghdiguian, Stephen, Gilles, Christine, Loncarek, Jadranka, Freiss, Gilles, Vignon, FranÇoise, Liaudet-Coopman, Emmanuelle
• Format: Journal Article Web Resource
• Language: English
• Published: United States Rockefeller University Press 31-01-2005; The Rockefeller University Press
• Subjects: Animals; Apoptosis; Apoptosis - physiology; Biochemistry, biophysics & molecular biology; Biochimie, biophysique & biologie moléculaire; Breast cancer; Butadienes; Butadienes - pharmacology; Cancer; Cathepsin D; Cathepsin D - genetics; Cathepsin D - metabolism; Cathepsin D - physiology; Cathepsin D - secretion; Cell Enlargement; Cell Enlargement - drug effects; Cell growth; Cell Growth Processes; Cell Growth Processes - drug effects; Cell Growth Processes - physiology; Cell Line; Cell Line, Tumor; Cell lines; Cell Movement; Cell Movement - drug effects; Cell Movement - physiology; Cell Proliferation; Cell Proliferation - drug effects; Cell Survival; Cell Survival - physiology; Cells; Cellular Biology; Coculture Techniques; Culture Media, Conditioned; Culture Media, Conditioned - pharmacology; Endocytosis; Endocytosis - drug effects; Enzyme Inhibitors; Enzyme Inhibitors - pharmacology; Enzyme P; Enzyme Precursors - metabolism; Enzyme Precursors - physiology; Enzyme Precursors - secretion; Epithelial cells; Fibroblasts; Fibroblasts - cytology; Fibroblasts - drug effects; Fibroblasts - ultrastructure; Humans; Life Sciences; Mannosephosphates - pharmacology; Mice; Microscopy, Electron; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Neoplasm Invasiveness; Neoplasms, Glandular and Epithelial - enzymology; Neoplasms, Glandular and Epithelial - pathology; Neoplasms, Glandular and Epithelial - secretion; Nitriles - pharmacology; Paracrine Communication - physiology; Phosphorylation - drug effects; Proteases; RNA, Small Interfering - genetics; Sciences du vivant; Small interfering RNA; Stromal cells; Transfection; Tumors; Wound Healing; protease; cancer; fibroblast; outgrowth; stroma
• ISSN: 0021-9525; 1540-8140; 1540-8140
• DOI: 10.1083/jcb.200403078

The aspartyl-protease cathepsin D (cath-D) is over-expressed 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.