[en] MT4-MMP expression in breast adenocarcinoma stimulates tumor growth and metastatic spreading to the lung. However whether these pro-tumorigenic and pro-metastatic effects of MT4-MMP are related to a proteolytic action is not known yet. Through site directed mutagenesis MT4-MMP has been inactivated in cancer cells through Glutamic acid 249 substitution by Alanine in the active site. Active MT4-MMP triggered an angiogenic switch at day 7 after tumor implantation and drastically accelerated subcutaneous tumor growth as well as lung colonization in RAG -/- mice. All these effects were abrogated upon MT4-MMP inactivation. In sharp contrast to most MMPs being primarily of stromal origin, we provide evidence that tumor-derived MT4-MMP, but not host-derived MT4-MMP contributes to angiogenesis. A genetic approach using MT4-MMP-deficient mice revealed that the status of MT4-MMP produced by host cells did not affect the angiogenic response. Despite of this tumor intrinsic feature, to exert its tumor promoting effect, MT4-MMP requires a permissive microenvironment. Indeed, tumor-derived MT4-MMP failed to circumvent the lack of an host angio-promoting factor such as lasminogen activator inhibitor (PAI-1). Overall, our study demonstrates the key contribution of MT4-MMP catalytic activity in the tumor compartment, at the interface with host cells. It identifies MT4-MMP as a key intrinsic tumor cell determinant that contributes to the elaboration of a permissive microenvironment for metastatic dissemination
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Host, Lorin
Paye, Alexandra ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biologie cellulaire et moléculaire appliquée à l'homme
Detry, Benoît ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biologie cellulaire et moléculaire appliquée à l'homme
Blacher, Silvia ; Université de Liège - ULiège > Département des sciences cliniques > Labo de biologie des tumeurs et du développement
Munaut, Carine ; Université de Liège - ULiège > Département des sciences cliniques > Labo de biologie des tumeurs et du développement
Foidart, Jean-Michel ; Université de Liège - ULiège > Département des sciences cliniques > Gynécologie - Obstétrique
Seiki, M.
Sounni, Nor Eddine ✱; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biologie cellulaire et moléculaire appliquée à l'homme
Noël, Agnès ✱; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biologie cellulaire et moléculaire appliquée à l'homme
✱ These authors have contributed equally to this work.
Language :
English
Title :
The proteolytic activity of MT4-MMP is required for its proangiogenic and pro-metastatic promoting effects
Publication date :
2012
Journal title :
International Journal of Cancer
ISSN :
0020-7136
eISSN :
1097-0215
Publisher :
Wiley Liss, Inc., New York, United States - New York
Volume :
131
Issue :
7
Pages :
1537-1548
Peer reviewed :
Peer Reviewed verified by ORBi
European Projects :
FP7 - 201279 - MICROENVIMET - Understanding and fighting metastasis by modulating the tumour microenvironment through interference with the protease network.
Kessenbrock K, Plaks V, Werb Z,. Matrix metalloproteinases: regulators of the tumor microenvironment. Cell 2010; 141: 52-67.
Egeblad M, Werb Z,. New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer 2002; 2: 161-74.
Sato H, Takino T, Okada Y, Cao J, Shinagawa A, Yamamoto E, Seiki M,. A matrix metalloproteinase expressed on the surface of invasive tumour cells. Nature 1994; 370: 61-5.
Sounni NE, Paye A, Host L, Noël A,. MT-MMPs as regulators of vessel stability associated with angiogenesis. Front Pharmacol 2011; 2: 111.
Sounni NE, Roghi C, Chabottaux V, Janssen M, Munaut C, Maquoi E, Galvez BG, Gilles C, Frankenne F, Murphy G, Foidart JM, Noel A,. Up-regulation of vascular endothelial growth factor-A by active membrane-type 1 matrix metalloproteinase through activation of Src-tyrosine kinases. J Biol Chem 2004; 279: 13564-74.
Sounni NE, Rozanov DV, Remacle AG, Golubkov VS, Noel A, Strongin AY,. Timp-2 binding with cellular MT1-MMP stimulates invasion-promoting MEK/ERK signaling in cancer cells. Int J Cancer 2010; 126: 1067-78.
D'Alessio S, Ferrari G, Cinnante K, Scheerer W, Galloway AC, Roses DF, Rozanov DV, Remacle AG, Oh ES, Shiryaev SA, Strongin AY, Pintucci G, et al. Tissue inhibitor of metalloproteinases-2 binding to membrane-type 1 matrix metalloproteinase induces MAPK activation and cell growth by a non-proteolytic mechanism. J Biol Chem 2008; 283: 87-99.
Puente XS, Pendas AM, Llano E, Velasco G, Lopez-Otin C,. Molecular cloning of a novel membrane-type matrix metalloproteinase from a human breast carcinoma. Cancer Res 1996; 56: 944-9.
Kajita M, Kinoh H, Ito N, Takamura A, Itoh Y, Okada A, Sato H, Seiki M,. Human membrane type-4 matrix metalloproteinase (MT4-MMP) is encoded by a novel major transcript: isolation of complementary DNA clones for human and mouse mt4-mmp transcripts. FEBS Lett 1999; 457: 353-6.
Gauthier MC, Racine C, Ferland C, Flamand N, Chakir J, Tremblay GM, Laviolette M,. Expression of membrane type-4 matrix metalloproteinase (metalloproteinase-17) by human eosinophils. Int J Biochem Cell Biol 2003; 35: 1667-73.
Funatsu N, Inoue T, Nakamura S,. Gene expression analysis of the late embryonic mouse cerebral cortex using DNA microarray: identification of several region- and layer-specific genes. Cereb Cortex 2004; 14: 1031-44.
Nuttall RK, Sampieri CL, Pennington CJ, Gill SE, Schultz GA, Edwards DR,. Expression analysis of the entire MMP and TIMP gene families during mouse tissue development. FEBS Lett 2004; 563: 129-34.
Plaisier M, Koolwijk P, Hanemaaijer R, Verwey RA, van der Weiden RM, Risse EK, Jungerius C, Helmerhorst FM, van Hinsbergh VW,. Membrane-type matrix metalloproteinases and vascularization in human endometrium during the menstrual cycle. Mol Hum Reprod 2006; 12: 11-8.
Rikimaru A, Komori K, Sakamoto T, Ichise H, Yoshida N, Yana I, Seiki M,. Establishment of an MT4-MMP-deficient mouse strain representing an efficient tracking system for MT4-MMP/MMP-17 expression in vivo using beta-galactosidase. Genes Cells 2007; 12: 1091-100.
Srichai MB, Colleta H, Gewin L, Matrisian L, Abel TW, Koshikawa N, Seiki M, Pozzi A, Harris RC, Zent R,. Membrane-type 4 matrix metalloproteinase (MT4-MMP) modulates water homeostasis in mice. PLoS One 2011; 6: e17099.
Patwari P, Gao G, Lee JH, Grodzinsky AJ, Sandy JD,. Analysis of ADAMTS4 and MT4-MMP indicates that both are involved in aggrecanolysis in interleukin-1-treated bovine cartilage. Osteoarthritis Cartil 2005; 13: 269-77.
Ariyoshi W, Takahashi N, Hida D, Knudson CB, Knudson W,. Mechanisms involved in enhancement of the expression and function of aggrecanases by hyaluronan oligosaccharides. Arthritis Rheum 2011;64:187-97.
Clements KM, Flannelly JK, Tart J, Brockbank SM, Wardale J, Freeth J, Parker AE, Newham P,. Matrix metalloproteinase 17 is necessary for cartilage aggrecan degradation in an inflammatory environment. Ann Rheum Dis 2011; 70: 683-9.
Chabottaux V, Sounni NE, Pennington CJ, English WR, van den Brule F, Blacher S, Gilles C, Munaut C, Maquoi E, Lopez-Otin C, Murphy G, Edwards DR, et al. Membrane-type 4 matrix metalloproteinase promotes breast cancer growth and metastases. Cancer Res 2006; 66: 5165-72.
Chabottaux V, Ricaud S, Host L, Blacher S, Paye A, Thiry M, Garofalakis A, Pestourie C, Gombert K, Bruyere F, Lewandowsky D, Tavitian B, et al. Membrane-type 4 matrix metalloproteinase (MT4-MMP) induces lung metastasis by alteration of primary breast tumor vascular architecture. J Cell Mol Med 2009; 13: 4002-13.
Huang CH, Yang WH, Chang SY, Tai SK, Tzeng CH, Kao JY, Wu KJ, Yang MH,. Regulation of membrane-type 4 matrix metalloproteinase by SLUG contributes to hypoxia-mediated metastasis. Neoplasia 2009; 11: 1371-82.
English WR, Puente XS, Freije JM, Knauper V, Amour A, Merryweather A, Lopez-Otin C, Murphy G,. Membrane type 4 matrix metalloproteinase (MMP17) has tumor necrosis factor-alpha convertase activity but does not activate pro-MMP2. J Biol Chem 2000; 275: 14046-55.
Rozanov DV, Hahn-Dantona E, Strickland DK, Strongin AY,. The low density lipoprotein receptor-related protein LRP is regulated by membrane type-1 matrix metalloproteinase (MT1-MMP) proteolysis in malignant cells. J Biol Chem 2004; 279: 4260-8.
Noel A, Boulay A, Kebers F, Kannan R, Hajitou A, Calberg-Bacq CM, Basset P, Rio MC, Foidart JM,. Demonstration in vivo that stromelysin-3 functions through its proteolytic activity. Oncogene 2000; 19: 1605-12.
Rozanov DV, Deryugina EI, Ratnikov BI, Monosov EZ, Marchenko GN, Quigley JP, Strongin AY,. Mutation analysis of membrane type-1 matrix metalloproteinase (MT1-MMP). The role of the cytoplasmic tail Cys(574), the active site Glu(240), and furin cleavage motifs in oligomerization, processing, and self-proteolysis of MT1-MMP expressed in breast carcinoma cells. J Biol Chem 2001; 276: 25705-14.
Valtanen H, Lehti K, Lohi J, Keski-Oja J,. Expression and purification of soluble and inactive mutant forms of membrane type 1 matrix metalloproteinase. Protein Expr Purif 2000; 19: 66-73.
Sounni NE, Devy L, Hajitou A, Frankenne F, Munaut C, Gilles C, Deroanne C, Thompson EW, Foidart JM, Noel A,. MT1-MMP expression promotes tumor growth and angiogenesis through an up-regulation of vascular endothelial growth factor expression. FASEB J 2002; 16: 555-64.
Noel A, De Pauw-Gillet MC, Purnell G, Nusgens B, Lapiere CM, Foidart JM,. Enhancement of tumorigenicity of human breast adenocarcinoma cells in nude mice by matrigel and fibroblasts. Br J Cancer 1993; 68: 909-15.
Maillard C, Jost M, Romer MU, Brunner N, Houard X, Lejeune A, Munaut C, Bajou K, Melen L, Dano K, Carmeliet P, Fusenig NE, et al. Host plasminogen activator inhibitor-1 promotes human skin carcinoma progression in a stage-dependent manner. Neoplasia 2005; 7: 57-66.
Masson VV, Devy L, Grignet-Debrus C, Bernt S, Bajou K, Blacher S, Roland G, Chang Y, Fong T, Carmeliet P, Foidart JM, Noel A,. Mouse aortic ring assay: a new approach of the molecular genetics of angiogenesis. Biol Proced Online 2002; 4: 24-31.
Blacher S, Devy L, Burbridge MF, Roland G, Tucker G, Noel A, Foidart JM,. Improved quantification of angiogenesis in the rat aortic ring assay. Angiogenesis 2001; 4: 133-42.
Blacher S, Detry B, Bruyere F, Foidart JM, Noel A,. Additional parameters for the morphometry of angiogenesis and lymphangiogenesis in corneal flat mounts. Exp Eye Res 2009; 89: 274-6.
Labrecque L, Nyalendo C, Langlois S, Durocher Y, Roghi C, Murphy G, Gingras D, Beliveau R,. Src-mediated tyrosine phosphorylation of caveolin-1 induces its association with membrane type 1 matrix metalloproteinase. J Biol Chem 2004; 279: 52132-40.
Itoh Y, Kajita M, Kinoh H, Mori H, Okada A, Seiki M,. Membrane type 4 matrix metalloproteinase (MT4-MMP, MMP-17) is a glycosylphosphatidylinositol- anchored proteinase. J Biol Chem 1999; 274: 34260-6.
Bajou K, Noel A, Gerard RD, Masson V, Brunner N, Holst-Hansen C, Skobe M, Fusenig NE, Carmeliet P, Collen D, Foidart JM,. Absence of host plasminogen activator inhibitor 1 prevents cancer invasion and vascularization. Nat Med 1998; 4: 923-8.
Overall CM, Tam E, McQuibban GA, Morrison C, Wallon UM, Bigg HF, King AE, Roberts CR,. Domain interactions in the gelatinase A.TIMP-2.MT1-MMP activation complex. The ectodomain of the 44-kDa form of membrane type-1 matrix metalloproteinase does not modulate gelatinase A activation. J Biol Chem 2000; 275: 39497-506.
Tam EM, Wu YI, Butler GS, Stack MS, Overall CM,. Collagen binding properties of the membrane type-1 matrix metalloproteinase (MT1-MMP) hemopexin C domain. The ectodomain of the 44-kDa autocatalytic product of MT1-MMP inhibits cell invasion by disrupting native type I collagen cleavage. J Biol Chem 2002; 277: 39005-14.
Sohail A, Marco M, Zhao H, Shi Q, Merriman S, Mobashery S, Fridman R,. Characterization of the dimerization interface of membrane type 4 (MT4)-matrix metalloproteinase. J Biol Chem 2011; 286: 33178-89.
Berndt S, Bruyer F, Jost M, Noel A,. In vitro and in vivo models of angiogenesis to dissect MMP function. In: The cancer degradome-proteases and cancer biology, 2008. 305.
Noel A, Jost M, Maquoi E,. Matrix metalloproteinases at cancer tumor-host interface. Semin Cell Dev Biol 2008; 19: 52-60.
Kruger A, Kates RE, Edwards DR,. Avoiding spam in the proteolytic internet: future strategies for anti-metastatic MMP inhibition. Biochim Biophys Acta 2010;1839:95-102.
Stratman AN, Saunders WB, Sacharidou A, Koh W, Fisher KE, Zawieja DC, Davis MJ, Davis GE,. Endothelial cell lumen and vascular guidance tunnel formation requires MT1-MMP-dependent proteolysis in 3-dimensional collagen matrices. Blood 2009; 114: 237-47.
Zhou Z, Apte SS, Soininen R, Cao R, Baaklini GY, Rauser RW, Wang J, Cao Y, Tryggvason K,. Impaired endochondral ossification and angiogenesis in mice deficient in membrane-type matrix metalloproteinase I. Proc Natl Acad Sci USA 2000; 97: 4052-7.
Sounni NE, Dehne K, van Kempen L, Egeblad M, Affara NI, Cuevas I, Wiesen J, Junankar S, Korets L, Lee J, Shen J, Morrison CJ, et al. Stromal regulation of vessel stability by MMP14 and TGFbeta. Dis Model Mech 2010; 3: 317-32.
Ito TK, Ishii G, Chiba H, Ochiai A,. The VEGF angiogenic switch of fibroblasts is regulated by MMP-7 from cancer cells. Oncogene 2007; 26: 7194-203.
El Hour M, Moncada-Pazos A, Blacher S, Masset A, Cal S, Berndt S, Detilleux J, Host L, Obaya AJ, Maillard C, Foidart JM, Ectors F, et al. Higher sensitivity of Adamts12-deficient mice to tumor growth and angiogenesis. Oncogene 2010; 29: 3025-32.
Devy L, Huang L, Naa L, Yanamandra N, Pieters H, Frans N, Chang E, Tao Q, Vanhove M, Lejeune A, van Gool R, Sexton DJ, et al. Selective inhibition of matrix metalloproteinase-14 blocks tumor growth, invasion, and angiogenesis. Cancer Res 2009; 69: 1517-26.
Scott CJ, Taggart CC,. Biologic protease inhibitors as novel therapeutic agents. Biochimie 2010; 92: 1681-8.
