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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.
This paper references
Cell extracts from CD55-/-SV40 and CD55-/-D231N cells were assayed for 6 h for proteolytic activity at pH 3.5 with [ 14 C]methemoglobin in the absence or presence of pepstatin
Plasminogen-related growth factor and semaphorin receptors: a gene superfamily controlling invasive growth.
P. Comoglio (1999)
Specific mannose-6-phosphate receptor-independent sorting of pro-cathepsin D in breast cancer cells.
F. Capony (1994)
Phosphorylation, glycosylation, and proteolytic activity of the 52-kD estrogen-induced protein secreted by MCF7 cells
F. Capony (1987)
Tumor-stroma interaction: positive feedback regulation of extracellular matrix metalloproteinase inducer (EMMPRIN) expression and matrix metalloproteinase-dependent generation of soluble EMMPRIN.
Yi Tang (2004)
Overexpression of transfected cathepsin D in transformed cells increases their malignant phenotype and metastatic potency.
M. Garcia (1990)
Stimulation of human extravillous trophoblast migration by IGF-II is mediated by IGF type 2 receptor involving inhibitory G protein(s) and phosphorylation of MAPK.
T. McKinnon (2001)
Cathepsin D maturation and its stimulatory effect on metastasis are prevented by addition of KDEL retention signal.
E. Liaudet (1994)
containing endocytosed [S 35 ]methionine-labeled cath-D were analyzed by SDS-PAGE after immunoprecipitation with M1G8 antibody
Effect of human procathepsin D on proliferation of human cell lines.
V. Vetvicka (1994)
Cathepsin D in breast cancer: a tissue marker associated with metastasis.
H. Rochefort (1992)
Know thy neighbor: stromal cells can contribute oncogenic signals.
T. Tlsty (2001)
Autocrine growth stimulation of the MCF 7 breast cancer cells by the estrogen-regulated 52 K protein.
F. Vignon (1986)
A novel metalloproteinase gene specifically expressed in stromal cells of breast carcinomas
P. Basset (1990)
Secreted cath-D proteolytic activity was obtained by subtracting the TCA soluble radioactivity obtained with pepstatin
proliferation of human cell lines
F. Vignon (1986)
Effect of human cathepsin D on proliferation of human cell lines
V. Vetvicka (1994)
The microenvironment of the tumour–host interface
L. Liotta (2001)
A mutated cathepsin-D devoid of its catalytic activity stimulates the growth of cancer cells
M. Glondu (2001)
Stromal cells can contribute oncogenic signals.
T. Tlsty (2001)
Upper panel: Cell extracts from CD55-/-cath-D and CD53+
Restricted expression of membrane type 1‐matrix metalloproteinase by myofibroblasts adjacent to human breast cancer cells
C. Bisson (2003)
Effects of pro-cath-D on MAP kinase pathway. Cells were cultured for 3 days in the presence of CM supplemented with 2% FCS and containing either no human cath-D (control)
EGF induces fibroblast contractility and motility via a PKCdelta -dependent pathway
A Iwabu (2004)
Control of invasive growth by hepatocyte growth factor (HGF) and related scatter factors.
L. Tamagnone (1997)
ml) were collected after 24 h incubation of transfected cells in 10% FCS medium in 6-well plates and cell extracts were prepared as described
cathepsin D-deficient mice
K. Nakashiro (2000)
Interaction of Human Breast Fibroblasts with Collagen I Increases Secretion of Procathepsin B*
J. Koblinski (2002)
Transfected cathepsin D stimulates high density cancer cell growth by inactivating secreted growth inhibitors.
E. Liaudet (1995)
Proteolytic activation of human procathepsin D.
G. Richo (1991)
Cathepsin D Triggers Bax Activation, Resulting in Selective Apoptosis-inducing Factor (AIF) Relocation in T Lymphocytes Entering the Early Commitment Phase to Apoptosis*
N. Bidère (2003)
Bottom panel: Conditioned media from transfected fibroblasts containing equivalent amount of proteins secreted by 24 h were assayed for 16 h for proteolytic activity
The microenvironment of the tumor-host interface
L. A. Liotta (2001)
Epidermal Growth Factor Induces Fibroblast Contractility and Motility via a Protein Kinase C δ-dependent Pathway*
A. Iwabu (2004)
Cell Signaling by Receptor Tyrosine Kinases
J. Schlessinger (2000)
Cells were tested for their ability to invade in the presence of CM containing no human cath-D (control) or 30 nM procath-D. Data are the mean s.d (n = 5 independent experiments). *, p < 0
The microenvironment of the tumor-host interface. Nature 411:375-379
L. A. Liotta (2001)
Lysosomal enzymes and their receptors.
K. von Figura (1986)
Relationship between cathepsin-D content and disease-free survival in node-negative breast cancer patients: a meta-analysis.
G. Ferrandina (1997)
In vitro degradation of extracellular matrix with Mr 52,000 cathepsin D secreted by breast cancer cells.
P. Briozzo (1988)
Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium
A. F. Olumi (1999)
After 4 days of culture, cell growth was analyzed by phase contrast microscopy. Experiments were performed in triplicate. Bars
Hepatocyte growth factor secreted by prostate-derived stromal cells stimulates growth of androgen-independent human prostatic carcinoma cells.
K. Nakashiro (2000)
Involvement of Nitric Oxide Released from Microglia–Macrophages in Pathological Changes of Cathepsin D-Deficient Mice
H. Nakanishi (2001)
Proteolytic activity of cath-D
Professor Brian Fox
D. Harnden (1999)
Cathepsin D in cancer metastasis: A protease and a ligand
H. Rochefort (1999)
Estrogen‐induced lysosomal proteases secreted by breast cancer cells: A role in carcinogenesis?
H. Rochefort (1987)
Improved quantification of angiogenesis in the rat aortic ring assay
S. Blacher (2004)
Cathepsin-D in primary breast cancer: prognostic evaluation involving 2810 patients
J. Foekens (1999)
Mice deficient for the lysosomal proteinase cathepsin D exhibit progressive atrophy of the intestinal mucosa and profound destruction of lymphoid cells.
P. Saftig (1995)
Two crystal structures for cathepsin D: the lysosomal targeting signal and active site.
P. Metcalf (1993)
Down-regulation of cathepsin-D by antisense gene transfer inhibits tumor growth and metastatic potential of human breast cancer cells
M. Glondu (2002)
Mapping replicational sites in the eucaryotic cell nucleus
H. Nakayasu (1989)
Fibroblasts, myofibroblasts, and wound contraction
F. Grinnell (1994)
Cytokine‐regulated urokinase‐type‐plasminogen‐activator (uPA) production by human breast fibroblasts in vitro
A. Sieuwerts (2004)
Cathepsin-D affects multiple steps of tumor progression: Proliferation, angiogenesis and apoptosis
G. J. Berchem (2002)
Prognostic value of cathepsin D in breast cancer
B. Westley (1999)
Down-regulation of cathepsin-D expression by antisense gene transfer inhibits tumor growth and experimental lung metastasis of human breast cancer cells
M. Glondu (2002)
Cathepsin-D affects multiple tumor progression steps in vivo: proliferation, angiogenesis and apoptosis
G. Berchem (2002)
New insights into the role of extracellular matrix during tumor onset and progression
S. Pupa (2002)
Breast stroma plays a dominant regulatory role in breast epithelial growth and differentiation: implications for tumor development and progression.
M. Shekhar (2001)
Involvement of two different cell death pathways in retinal atrophy of cathepsin D-deficient mice
M. Koike (2003)
Epidermal growth factor induces fibroblast contractility and motility via a PKCdelta -dependent pathway
A. Iwabu (2004)
Highly consistent genetic alterations in childhood adrenocortical tumours detected by comparative genomic hybridization
L. James (1999)
Ras and Rho GTPases A Family Reunion
D. Bar-Sagi (2000)
Heterotypic signaling between epithelial tumor cells and fibroblasts in carcinoma formation.
B. Elenbaas (2001)
Endocytosis of pro-cathepsin D into breast cancer cells is mostly independent of mannose-6-phosphate receptors.
V. Laurent-Matha (1998)
Host microenvironment in breast cancer development: Epithelial–mesenchymal transition in breast cancer development
A. Vincent-Salomon (2003)
Fibroblasts capture cathepsin D secreted by breast cancer cells: possible role in the regulation of the invasive process.
N. Heylen (2002)
MMP-2 and MMP-9 Expression in Breast Cancer-Derived Human Fibroblasts is Differentially Regulated by Stromal-Epithelial Interactions
Christian F. Singer (2004)
Effects of pro-cath-D on fibroblast outgrowth
In Vivo Evidence That the Stromelysin-3 Metalloproteinase Contributes in a Paracrine Manner to Epithelial Cell Malignancy
R. Masson (1998)
Molecular aspects of the endocytic pathway.
M. Clague (1998)
Carcinoma-associated fibroblasts stimulate tumor progression of initiated human epithelium
AF Olumi (2000)
This paper is referenced by
Neurotoxicity of microglial cathepsin D revealed by secretome analysis
Sangseop Kim (2007)
Cathepsin D: newly discovered functions of a long-standing aspartic protease in cancer and apoptosis.
E. Liaudet-Coopman (2006)
A Mouse Stromal Response to Tumor Invasion Predicts Prostate and Breast Cancer Patient Survival
M. Bacac (2006)
Nuclear cathepsin D enhances TRPS1 transcriptional repressor function to regulate cell cycle progression and transformation in human breast cancer cells
Anne-Sophie Bach (2015)
Secretion of cytokines in breast cancer cells: the molecular mechanism of procathepsin D proliferative effects.
M. Fusek (2007)
A cancer cell metalloprotease triad regulates the basement membrane transmigration program.
K. Hotary (2006)
Role of altered pH homeostasis and hypoxia in the phenotypic changes of cancer cells
N. Kokkonen (2009)
Search for cancer treatment continues: Procathepsin D
A. Vashishta (2012)
Cathepsin D acts as an essential mediator to promote malignancy of benign prostatic epithelium
F. Pruitt (2013)
Cathepsin D expression level affects alpha-synuclein processing, aggregation, and toxicity in vivo
V. Cullen (2008)
IFN‐γ regulation of vacuolar pH, cathepsin D processing and autophagy in mammary epithelial cells
Z. Khalkhali-Ellis (2008)
Epigallocatechin-3-gallate exhibits anti-fibrotic effect by attenuating bleomycin-induced glycoconjugates, lysosomal hydrolases and ultrastructural changes in rat model pulmonary fibrosis.
N. Sriram (2009)
Immunohistochemical expression of cathepsin D and matrix metalloproteinase-9 in common epidermal tumors
A. M. Hassan (2014)
Cathepsin D Deficiency - Molecular and Cellular Mechanisms of Neurodegeneration
S. Partanen (2006)
Pathophysiological functions of cathepsin D: Targeting its catalytic activity versus its protein binding activity?
O. Masson (2010)
Haematopoietic development and immunological function in the absence of cathepsin D
Calogero Tulone (2007)
Cathepsins and HtrAs – Multitasking Proteases in Programmed Cell Death
Lalith K. Chaganti (2015)
Proteolysis of cystatin C by cathepsin D in the breast cancer microenvironment
V. Laurent-Matha (2012)
Acid phosphatase and cathepsin D are active expressed enzymes in the placenta of the cat.
C. K. Minazaki (2008)
Antitumor and antimetastatic activity of fucoidan, a sulfated polysaccharide isolated from the Okhotsk sea Fucus evanescens brown alga
T. V. Alekseyenko (2007)
A Novel Role of Oncostatin M in Invasive Breast Cancer: Induction of Cathepsin D and Lysosomal Trafficking
Jordan Koncinsky (2013)
Regulation of angiogenic processes in omental endothelial cells during metastasis of epithelial ovarian cancer
Zahidul Islam Pranjol (2017)
Procathepsin D expression correlates with invasive and metastatic phenotype of MDA-MB-231 derived cell lines.
Sujata Saraswat Ohri (2007)
A Novel Strategy to Investigate Tissue‐Secreted Tumor Microenvironmental Proteins in Serum toward Development of Breast Cancer Early Diagnosis Biomarker Signature
Namita Pendharkar (2019)
Effect of procathepsin D activation peptide on gene expression of breast cancer cells.
P. Benes (2006)
Mesenchymal stem cell homing towards cancer cells is increased by enzyme activity of cathepsin D.
Gowthami Vangala (2019)
Cathepsin D enhances breast cancer invasion and metastasis through promoting hepsin ubiquitin-proteasome degradation.
C. Zhang (2018)
Relaxin enhances the oncogenic potential of human thyroid carcinoma cells.
S. Hombach‐Klonisch (2006)
Ribozyme-targeting procathepsin D and its effect on invasion and growth of breast cancer cells: an implication in breast cancer therapy.
A. Vashishta (2007)
Human Herpesvirus 8 Interleukin-6 Contributes to Primary Effusion Lymphoma Cell Viability via Suppression of Proapoptotic Cathepsin D, a Cointeraction Partner of Vitamin K Epoxide Reductase Complex Subunit 1 Variant 2
D. Chen (2013)
Effect of ovarian cancer ascites on cell migration and gene expression in an epithelial ovarian cancer in vitro model.
L. Meunier (2010)
Pro-cathepsin D interacts with the extracellular domain of the β chain of LRP1 and promotes LRP1-dependent fibroblast outgrowth
M. Beaujouin (2010)See more