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Published online 24 January 2005. doi:10.1083/jcb.200403078
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 168, Number 3, 489-499
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Article

 Catalytically inactive human cathepsin D triggers fibroblast invasive growth

Valérie Laurent-Matha1, Sharon Maruani-Herrmann1, Christine Prébois1, Mélanie Beaujouin1, Murielle Glondu1, Agnès Noël2, Marie Luz Alvarez-Gonzalez2, Sylvia Blacher2, Peter Coopman3, Stephen Baghdiguian4, Christine Gilles2, Jadranka Loncarek5, Gilles Freiss1, Françoise Vignon1, and Emmanuelle Liaudet-Coopman1

1 INSERM U540 Endocrinologie Moléculaire et Cellulaire des Cancers, Université de Montpellier 1, 34090 Montpellier, France
2 Laboratory of Tumor and Developmental Biology, University of Liège, Sart-Tilman, B-4000 Liège, Belgium
3 CNRS UMR 5539, Université Montpellier 2, 34095 Montpellier, France
4 CNRS UMR 5554, Université Montpellier 2, 34095 Montpellier, France
5 INSERM EMI 0229, Centre de Recherche en Cancérologie, CRLC Val d'Aurelle-Paul Lamarque, 34298 Montpellier, France

Correspondence to E. Liaudet-Coopman: liaudet{at}montp.inserm.fr

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.

V. Laurent-Matha and S. Maruani-Hermann contributed equally to this work.

Sharon Maruani-Herrmann's present address is Dina Raveh's laboratory, Life Science Dept., Ben Gourion University of the Negev, Beer-Sheva 84105, Israel.

V. Laurent-Matha's present address is Cellular Biology Unit, IGH, CNRS UPR 1142, 34396 Montpellier, Cedex 05, France.

Abbreviations used in this paper: 3D, three-dimensional; cath-D, cathepsin D; HMF, human mammary fibroblast; luc siRNA, luciferase siRNA; Man-6-P, Mannose-6-phosphate.


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