The Epithelial-Mesenchymal Transition.pdf

162 Cell 145,April 1,2011 2011 Elsevier Inc.DOI 10.1016/j.cell.2011.03.029See online version for legend and references.SnapShot:The Epithelial-Mesenchymal TransitionJonathan P.Sleeman3,4 and Jean Paul Thiery2,31IMCB and Experimental Therapeutics Centre,Biopolis A*STAR,138673 Singapore;2Cancer Science Institute,117456 Singapore 3University of Heidelberg,Medical Faculty Mannheim,D-68167 Mannheim,Germany;4Karlsruhe Institute of Technology,Postfach 3640,76021 Karlsruhe,GermanyLaminin 5TRITRITRIISnail1/2Zeb1/2Par3Par6aPKCBMPsBMPR1BMPR2PatchedGrowthfactorsIL-6JAG2JAMp120-Catp53RhoACdc42RhoARhoAPDGFCdc42Cdc42Glu-tubulinRac1Par6Par3aPKCClaudinJAMOccludinClaudinOccludinZO3ZO1ZO2ActinIQGAPE-cadherinNectin-cat-cat-cat-cat-cat-catAfadinF-actinVinculinX-ActininClip170Dynein/dynactincomplexmiR-200FOXA1/2BASEMENT MEMBRANEROCKDDR1Collectivecellmigrationp190RhoGAPDAP21PGSK3RhoARhoEMyosinlightchainHIF 1/2LoxL2E2.2KLF8FOXQ1E47GSCTwistSnail1/2Snail1/2Smad2/3HedgehogERPAK1STAT3IL-6RPI3KRasRTKLIV1AKTMAPKNF-BNF-BCSLGli1MTA3Zeb1/2miR-205miR-200 miR-205E-cadherin and otherdownregulated genes(see box A)Upregulated genes(see box B)E-cadherinDesmosomeCytokeratinGap junctionPlakoglobinDesmoplakinBalancedactivitiesTight junctionEPITHELIALMESENCHYMALMESENCHYMALAdherens junctionStabilized actincytoskeletonApicobasalmicrotubulesp120-Catp120-CatKaisop120-Catp120-CatGSK3DishevelledLRP5/6FrizzledNectinAfadinRTKDDR1Collagen 1MMPsNCAMN-cadPDGFRTranscriptionFocaladhesionformationAdherensjunctiondisassemblyFilopodiaLamellipodiaMigrationInvasionECM remodellingFocal adhesionassembly and turnoverExamples of up-regulated genesTRIVimentinSMAN-cadherinNCAMFibronectinLamininsmiR-661MMPsExamples of down-regulated genesTubulin tyrosine ligaseClaudinsOccludinsZO1/ZO3Crumbs3DesmoplakinConnexin43E-cadherinNectin-1VE-cadherinCytokeratinsCollagen I,IIOther EMT-associated effectsResistance to senescenceResistance to apoptosisTherapy resistanceStemnessCytoskeletonremodelingMembraneruffesLoss ofdesmosomesMicrotentaclesDissociation oftight junctionsLoss of gapjunctionsEndocytosisdegradationFocal adhesionformationIncreasedTGF-signalingE-cadherindegradationBasement membrane degradationEB1Nineinp190RhoGAPp190RhoGAPSmurf1-catRap1FAKFAKFAKFynRac1bHypoxiaRac1Rac1ReactiveoxygenspeciesPyk2ILKAKTDAB2p130CAS-catABOther EMT-inducing pathwaysILEIEndothelin-A receptor-PI3KTNF-NF-B,AktHyaluronic acidCOX2-PGE2AMFPTH(rP)RBile acidsNicotineUV irradiationSCFAxl-Gas6PlectinWntFAKHakaiRhoAProteasomeCK1EPar3Par6c-srcc-srcZO3ZO1ZO2MyosinlightchainDesmosomePSmad2/3PSnail1/2PProteasomeProteasomeProteasomeProteasomeProteasomeProteasomeProteasomeP-catCK1-catPUbRhoASnail1/2RhoAProteasomeProteasomeProteasomeUbFAKILKPPFynFynPT RITRIIaPKCPar3Par6P-catc-srcPIntegrin64Integrin64DesmogleinDesmogleinDesmocollinDesmocollinNOTCHNOTCHSmoothenedSmoothenedTGF-TGF-Six1SnapShot:The Epithelial-Mesenchymal TransitionJonathan P.Sleeman3,4 and Jean Paul Thiery1,21IMCB and Experimental Therapeutics Centre,Biopolis A*STAR,138673 Singapore2Cancer Science Institute,117456 Singapore 3University of Heidelberg,Medical Faculty Mannheim,D-68167 Mannheim,Germany4Karlsruhe Institute of Technology,Postfach 3640,76021 Karlsruhe,Germany162.e1 Cell 145,April 1,2011 2011 Elsevier Inc.DOI 10.1016/j.cell.2011.03.029This SnapShot portrays important regulatory pathways and major cellular events that are activated during the transition from an epithelial to a mesenchymal morphology during development and disease.The cell on the left represents the epithelial state,whereas the central cell depicts transcriptional regulatory networks that orchestrate the process of epithelial-to-mesenchymal transition(EMT).The cell on the right illustrates some of the consequences of the activity of these networks that endow formerly epithelial cells with mesenchymal characteristics.Note that this overview does not take into account cell-type-specific regulation of EMT,and that not all illustrated mechanisms are obligate for EMT to occur.The temporal regulation of the EMT process is also not considered in this SnapShot.The Epithelial PhenotypePolarized epithelial cells are typified by tight junctions,adherens junctions,desmosomes,and gap junctions.Junctional complexes not only act as mediators of polarized cell-cell contacts but also serve as anchor points for the actin cytoskeleton.Adherens junctions can additionally anchor apicobasal microtubule arrays,and through E-cadherin-DDR1 interactions are also involved in collective cell migration.Organization of the actin cytoskeleton,microtubule arrays,and cell-cell junctions is tightly coordinated in a mechanism that probably involves IQGAP,but the details remain to be investigated.Balanced regulation of the activities of RhoA(stress fibers),Cdc42(filopodia),and Rac1(lamellipodia)stabilizes the actin cytoskeleton and maintains the epithelial phenotype.Epithelial cells are tethered to the underlying basement membrane,for example through integrins.The repression of EMT-inducing transcriptional regulators(for example,through microRNAs),as well the activity of positively acting factors such as FOXA1/2,ensures that expression of key junctional proteins such as E-cadherin is maintained.Suppression of GSK3 also helps to maintain the epithelial phenotype.Transcriptional Activation of EMTA variety of extracellular stimuli have the potential to induce EMT.A complex network of positively and negatively acting signal transduction mechanisms converge on the nucleus to downregulate genes required for the epithelial phenotype and to upregulate genes that specify mesenchymal characteristics.GSK3 and NF-B play central roles in coordinating these pathways.Members of the Snail family of transcriptional regulators,namely Snail1 and Snail2,have emerged as a key regulatory node.The zinc finger transcription factors Zeb1 and Zeb2 also make a pivotal contribution to this regulation.EMT-inducing signals promote their expression,regulate their stability,and/or alter their subcellular location.Loss of Epithelial and Acquisition of Mesenchymal CharacteristicsKey targets of the pathways that induce EMT include the adherens junction components E-cadherin and-catenin.In addition to being transcriptionally downregulated and epigenetically switched off,E-cadherin can be proteolytically cleaved and targeted to endosomes for degradation.Proteosomal degradation of-catenin destabilizes adherens junctions,whereas loss of E-cadherin can increase the free pool of-catenin that can then enter the nucleus and modulate transcription.An important consequence of EMT-inducing transcriptional modulation as well as other pro-EMT processes is the loss of the junctional complexes that typify polarized epithelial cells.Enhanced activation of the GTPases Cdc42 and Rac1 and suppression of RhoA favor the formation of lamellipodia and filopodia,migration,and invasion.A variety of mechanisms promote the assembly and turnover of focal adhesions.Extensive cytoskeleton remodeling occurs,including switching from a predominantly cytokeratin to a vimentin-rich intermediate filament net-work.Detyrosination of tubulin promotes microtentacle formation.Proteolytic enzymes are produced that together with increased expression of extracellular matrix components serve to remodel the microenvironment surrounding the cells.Other properties endowed on cells undergoing EMT include resistance to apoptosis,senescence,and therapeutics and the acquisition of stemness characteristics.AcknowledgmentsThis work was supported by a grant to J.P.S.from the European Union under the auspices of the FP7 collaborative project TuMIC,contract no.HEALTH-F2-2008-201662.RefeRencesCasas,E.,Kim,J.,Bendesky,A.,Ohno-Machado,L.,Wolfe,C.J.,and Yang,J.(2011).Snail2 is an essential mediator of Twist1-induced epithelial mesenchymal transition and me-tastasis.Cancer Res.71,245254.Chang,C.J.,Chao,C.H.,Xia,W.,Yang,J.Y.,Xiong,Y.,Li,C.W.,Yu,W.H.,Rehman,S.K.,Hsu,J.L.,Lee,H.H.,et al.(2011).p53 regulates epithelial-mesenchymal transition and stem cell properties through modulating miRNAs.Nat.Cell Biol.13,317323.Hanahan,D.,and Weinberg,R.A.(2011).Hallmark of cancers:the next generation.Cell 144,646674.Hidalgo-Carcedo,C.,Hooper,S.,Chaudhry,S.I.,Williamson,P.,Harrington,K.,Leitinger,B.,and Sahai,E.(2011).Collective cell migration requires suppression of actomyosin at cell-cell contacts mediated by DDR1 and the cell polarity regulators Par3 and Par6.Nat.Cell Biol.13,4958.Peinado,H.,Olmeda,D.,and Cano,A.(2007).Snail,Zeb and bHLH factors in tumour progression:an alliance against the epithelial phenotype?Nat.Rev.Cancer 7,415428.Schmalhofer,O.,Brabletz,S.,and Brabletz,T.(2009).E-cadherin,beta-catenin,and ZEB1 in malignant progression of cancer.Cancer Metastasis Rev.28,151166.Thiery,J.P.,and Sleeman,J.P.(2006).Complex networks orchestrate epithelial-mesenchymal transitions.Nat.Rev.Mol.Cell Biol.7,131142.Thiery,J.P.,Acloque,H.,Huang,R.Y.,and Nieto,M.A.(2009).Epithelial-mesenchymal transitions in development and disease.Cell 139,871890.Whipple,R.A.,Matrone,M.A.,Cho,E.H.,Balzer,E.M.,Vitolo,M.I.,Yoon,J.R.,Ioffe,O.B.,Tuttle,K.C.,Yang,J.,and Martin,S.S.(2010).Epithelial-to-mesenchymal transition promotes tubulin detyrosination and microtentacles that enhance endothelial engagement.Cancer Res.70,81278137.Yilmaz,M.,and Christofori,G.(2009).EMT,the cytoskeleton,and cancer cell invasion.Cancer Metastasis Rev 28,15-33.