Cancer du sein et micro-environnement tumoral: rôle de la protéase ...

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Cathepsin D is a new ligand for extracellular domain of LRP1 b chain andpromotes LRP1-dependent fibroblast outgrowthMélanie Beaujouin 1 , Christine Prébois 1 , Danielle Derocq 1 , Valérie Laurent-Matha 1 ,Olivier Masson 1 , Sophie Pattingre 1 , Peter Coopman 2 , Nadir Bettache 2 , JamiGrossfield 3 , Robert E. Hollingsworth 3 , Hongyu Zhang 4 , Zemin Yao 4 , Bradley THyman 5 , Peter van der Geer 6 , Gary K Smith 7 , and Emmanuelle Liaudet-Coopman 1* .1 IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, F-34298,France; INSERM, U896, Montpellier, F-34298, France; Université Montpellier1,Montpellier, F-34298, France; CRLC Val dAurelle Paul Lamarque, Montpellier, F-34298, France. 2 Centre de Recherche de Biochimie Macromoléculaire, CNRS UMR5237, Université Montpellier 2, 34293 Montpellier Cedex 5, France. 3 GeneticsResearch, GlaxoSmithKline, Inc. Five Moore Drive, Research Triangle Park, NorthCarolina, 27709, USA. 4 Department of Biochemistry, Microbiology and Immunology,University of Ottawa, Ottawa K1Y4W7, Canada. 5 Alzheimer Disease ResearchLaboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown,Massachusetts 02129, USA. 6 Department of Chemistry and Biochemistry, San DiegoState University, 5500 Campanile Drive, MC 1030, San Diego, CA 92182-1030, USA.7 Screening and Compound Profiling, GlaxoSmithKline, Inc. Five Moore Drive,Research Triangle Park, North Carolina, 27709, USA.*Corresponding author: E Liaudet-Coopman, Inserm U896, IRCM Val d'Aurelle-Paul Lamarque, 34298 Montpellier Cedex 5, France ; Tel (33) 467 61 24 23 ; FAX(33) 467 31 37 87 ; E-mail: emmanuelle.liaudet-coopman@inserm.frRunning title: cath-D promotes LRP1-dependent fibroblast outgrowthKey words: cancer, fibroblast, cathepsin, LRP1, tumor micro-environment1
ABSTRACTThe aspartic protease cathepsin-D (cath-D) is highly secreted by breast cancer cellsand triggers fibroblast outgrowth via a paracrine loop. Here, we demonstrate that theLDL receptor-related protein-1, LRP1, is the cath-D fibroblastic receptor. Cath-Dbinds to residues 349-394 of LRP1b and is therefore the first identified ligand of theextra-cellular domain of the b chain of LRP1. Interaction occurs at the cell surfaceand in vesicle-like structures. Cath-D is partially endocytosed by LRP1 in fibroblasts.Our results revealed that the ability of secreted cath-D to promote fibroblastoutgrowth depends on LRP1 expression. These observations demonstrate that procath-Dsecreted by epithelial cancer cells promotes fibroblast outgrowth in aparacrine LRP1-dependent manner in the breast tumour micro-environment.2
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Université Montpellier I UFR Méd
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Un grand merci à tous mes collabor
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TitleBreast cancer and tumoral micr
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Cancer du sein et micro-environneme
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C. PRESENTATION DU TRAVAIL DE THESE
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But de la thèseLa cathepsine-D (ca
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I. Le tissu adipeux1) Généralité
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(Adenosine triphosphate). Cette pro
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Cette synthèse de novo a lieu dans
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ABFigure 6 : Schéma de la oxydati
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d. Ladipocyte : une cellule sécré
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3) Ladipogenèsea. Les différentes
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. Les facteurs de transcriptionLa d
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Lexpression de C/EBP est quant à e
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adipeux. Les analyses histologiques
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adipocyteFigure 10 : Schéma repré
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II. La cathepsine-D1) Synthèse, ma
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les cath-B et L, en une forme matur
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Il existe deux RM6P : le RM6P/IGFII
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2) Fonctions de la cath-Da. Dans la
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. Dans les pathologiesEn plus de se
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c. Rôles et mécanismes daction da
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carcinome de prostate serait respon
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La cath-D joue donc un rôle import
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Une fois le marquage des peptides e
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Afin de réaliser ce projet, nous a
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III. Le récepteur LRP11) Organisat
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2) Trafic intra-cellulaireComme le
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LRP1αLRP1Membrane associatedprotea
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Tableau 3 : Ligands connus du LRP1(
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I. Etude du rôle de la cathepsine
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Cathepsin-D, a key protease in brea
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IntroductionConsumption of meals ri
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(Fig. 1A, panel a). This differenti
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differentiated adipocyte (Fig. 4B).
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DiscussionOur results demonstrate t
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from normal and peri-al breast adip
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mouse RS9 (sens 5CGGCCCGGGAGCTGTTGA
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agreement of local ethic committee.
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Statistical analysis. Results are e
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Loncarek J, Freiss G, Vignon F and
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Aa3000 *b4000*B8000**cath-D mRNA(ar
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ABcath-D mRNA(ratio RS9)PPARg mRNA(
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A D3 D7 D14D0BaD0 D3 D7 D14D0 D3 D7
Page 90 and 91: AshLucshcath-DF442A C34 C37 A4 D10c
Page 92 and 93: AF442-AC34C37A4D10BF442-AC34C37A4D1
Page 94 and 95: II. Etude du rôle du LRP1 dans les
Page 96 and 97: 2) Article 2:LRP1 receptor controls
Page 98 and 99: LRP1, Adipogenesis, Obesityrelative
Page 100 and 101: LRP1, Adipogenesis, ObesityFigure 3
Page 102 and 103: LRP1, Adipogenesis, ObesityFigure 5
Page 104 and 105: LRP1, Adipogenesis, ObesitySome ins
Page 106 and 107: LRP1, Adipogenesis, ObesityLipolysi
Page 108 and 109: CONCLUSIONLa cathepsine D (cath-D)
Page 110 and 111: la souris obèses. Enfin, linhibiti
Page 112 and 113: carcinogénique sont encore mal con
Page 114 and 115: Ce travail de thèse a étudié, po
Page 116 and 117: REFERENCESAhima, R. S. (2006). Adip
Page 118 and 119: implicates them as antigen presenti
Page 120 and 121: Cataldo, A. M., Barnett, J. L., Ber
Page 122 and 123: Folkman, J. (2003). Fundamental con
Page 124 and 125: Hofmann, S. M., Zhou, L., Perez-Til
Page 126 and 127: Langin, D. (2006a). Adipose tissue
Page 128 and 129: Ludwig, T., Ovitt, C. E., Bauer, U.
Page 130 and 131: Nirde, P., Derocq, D., Maynadier, M
Page 132 and 133: Rozanov, D. V., Hahn-Dantona, E., S
Page 134 and 135: Taleb, S., Cancello, R., Clement, K
Page 136 and 137: Xiao, Y., Junfeng, H., Tianhong, L.
Page 138 and 139: F. ANNEXE98
Page 142 and 143: INTRODUCTIONLysosomal aspartic prot
Page 144 and 145: pcDNA3.1(+)Myc-tagged LRP1b into pc
Page 146 and 147: (Protein refolding kit, Novagen) fo
Page 148 and 149: anti-mouse-gold (Aurion). Sections
Page 150 and 151: not secrete detectable levels of pr
Page 152 and 153: using cath-D-/- MEF transfected wit
Page 154 and 155: co-culture outgrowth assays with ca
Page 156 and 157: REFERENCES1. Vignon, F., Capony, F.
Page 158 and 159: steps in vivo: proliferation, angio
Page 160 and 161: 28. Laurent-Matha, V., Lucas, A., H
Page 162 and 163: 42. Zurhove, K., Nakajima, C., Herz
Page 164 and 165: Figure 1. Cath-D interacts with the
Page 166 and 167: Figure 2. Cath-D binds to residues
Page 168 and 169: Figure 3. Cath-D interacts with LRP
Page 170 and 171: Figure 5. Silencing LRP1 in cath-D
Page 172 and 173: Figure 1. Cath-D interacts with the
Page 174 and 175: Figure 6. LRP1 is the receptor medi
Page 176 and 177: Beaujouin, Figure Sup. 2cath-D-/-ME
Page 178: RésuméLaspartyl protéase catheps
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