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J. Cell Biol. 168 (3): 489-499

Copyright © 2005 by the Rockefeller University Press.

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

Abstract: 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.

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Proteolysis of cystatin C by cathepsin D in the breast cancer microenvironment.
V. Laurent-Matha, P. F. Huesgen, O. Masson, D. Derocq, C. Prebois, M. Gary-Bobo, F. Lecaille, B. Rebiere, G. Meurice, C. Orear, et al. (2012)
FASEB J 26, 5172-5181
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Procathepsin D and Cytokines Influence the Proliferation of Lung Cancer Cells.
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Pro-cathepsin D interacts with the extracellular domain of the {beta} chain of LRP1 and promotes LRP1-dependent fibroblast outgrowth.
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J. Cell Sci. 123, 3336-3346
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The expression of prolactin and its cathepsin D-mediated cleavage in the bovine corpus luteum vary with the estrous cycle.
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Am J Physiol Endocrinol Metab 293, E1365-E1377
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The Role of S100P in the Invasion of Pancreatic Cancer Cells Is Mediated through Cytoskeletal Changes and Regulation of Cathepsin D.
H. J. Whiteman, M. E. Weeks, S. E. Dowen, S. Barry, J. F. Timms, N. R. Lemoine, and T. Crnogorac-Jurcevic (2007)
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A cancer cell metalloprotease triad regulates the basement membrane transmigration program.
K. Hotary, X.-Y. Li, E. Allen, S. L. Stevens, and S. J. Weiss (2006)
Genes & Dev. 20, 2673-2686
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Processing of human cathepsin d is independent of its catalytic function and auto-activation: involvement of cathepsins L and B..
V. Laurent-Matha, D. Derocq, C. Prebois, N. Katunuma, and E. Liaudet-Coopman (2006)
J. Biochem. 139, 363-371
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Catalytically inactive human cathepsin D triggers fibroblast invasive growth.
V. Laurent-Matha, S. Maruani-Herrmann, C. Prebois, M. Beaujouin, M. Glondu, A. Noel, M. L. Alvarez-Gonzalez, S. Blacher, P. Coopman, S. Baghdiguian, et al. (2005)
J. Exp. Med. 201, i6-6
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