肿瘤干细胞异质性的综述cellLeadingEdgeEssay822Cell138,September4,2022?2022ElsevierInc.WhatIstheCancerStemCellModel?Todevisemoreeffectivecancerther-apiesitwillbecriticaltodeterminewhichcancercellshavethepotentialtocontributetodiseaseprogression.Ifmostcancercellscanproliferateexten-sivelyandmetastasize,thenvirtuallyallcellsmustbeeliminatedtocurethedisease.Consistentwiththisview,tra-ditionalcancertherapieshavesoughttoeliminateasmanycancercellsaspossible.Incontrasttothisapproach,thecancerstemcellmodelproposesthatthegrowthandprogressionofmanycancersaredrivenbysmallsub-populationsofcancerstemcells(Reyaetal.,2001;Dick,2022).Thecancerstemcellmodeldoesnotaddressthequestionofwhethercancersarisefromnormalstemcells.Rather,itsuggeststhatirrespectiveofthecell-of-origin,manycancersmaybehierarchicallyorganizedinmuchthesamemannerasnormaltissues.Justasnormalstemcellsdifferentiateintophenotypicallydiverseprogenywithlimitedprolifera-tivepotential,itisarguedthatcancerstemcellsalsoundergoepigeneticchangesanalogoustothedifferentia-tionofnormalcells,formingphenotyp-icallydiversenontumorigeniccancercellsthatcomposethebulkofcellsinatumor.Theseepigeneticchangesareproposedtobeassociatedwithanirreversible(orrarelyreversible)lossoftumorigeniccapacitysuchthatthevastmajorityofcellsinthesecancershavelittlecapacitytocontributetodis-easeprogression.Tocharacterizeandeliminatethemalignantcellsincancersthatfollowthismodel,itisnecessarytofocusonthesmallsubpopulationsoftumorigeniccells.Consistentwiththecancerstemcellmodel,certaincancers(includingsomegermcellcancersandsomeleukemias)havebeenrecognizedfordecadestoincludeneoplasticcellsthatdifferenti-ateintopost-mitoticderivatives.Germcellcancersgiverisetohighlydiffer-entiatedcells,suchasthosethatmakeneuraltissue(IllmenseeandMintz,1976).Someleukemiasgiverisetohighlydifferentiatedhematopoieticcells(Fearonetal.,11016;Barabeetal.,2007).Thesecancersareobviouslyhierarchicallyorganized.Themorecontroversialquestionraisedbyrecentstudiesiswhethermanyothercancersexhibitasimilarhierarchicalorganiza-tion,evenwhenovertdifferentiationisnotevidentamongthecancerhttps://www.sodocs.net/doc/7d9770465.htmlpellingdatasupportthecan-cerstemcellmodelinvarioushumancancersincludingmalignantgermcellcancers(KleinsmithandPierce,1964;IllmenseeandMintz,1976),leu-kemias(Lapidotetal.,11014;BonnetandDick,11017),breastcancers(Al-Hajjetal.,2003),braincancers(Singhetal.,2004),andcoloncancers(Dal-erbaetal.,2007;O’Brienetal.,2007;Ricci-Vitianietal.,2007).Ineachcase,onlysmallsubpopulationsofcellscantransferdiseaseupontransplantationintoimmunocompromisedNOD/SCIDmice,andmarkershavebeenidentifiedthatdistinguishtheleukemogenic/tum-origeniccancercellsfromthebulkpop-ulationsofnonleukemogenic/tumori-geniccells.Theabilitytopredictwhichcellsaretumorigenicbasedonmarkerexpressionindicatesthatthetumori-geniccellsareintrinsicallydifferentfromnontumorigeniccancercells.Yet,noclearmorphologicaldistinctionwasfoundbetweentumorigenicandnontu-morigenicbreastcancercells(Al-Hajjetal.,2003),implyingthatdifferentia-tionneednotbeovertforthecellstobehierarchicallyorganized.Theobserva-tionthattumorigeniccellshavetendedtoberareinthecancersfoundsofartofollowacancerstemcellmodelimpliesthatepigeneticdifferencesdistinguishtumorigenicfromnontumorigeniccellsbecauseitisimplausiblethatonlyrarecancercellshaveagenotypepermis-siveforextensiveproliferation.Tum-origeniccancerstemcellsalsoformphenotypicallydiversenontumorigeniccells,recapitulatingatleastsomeoftheheterogeneityinthetumorsfromwhichtheyderive.Despitestrongdatasupportingthestemcellmodelinsomecancers,itisimportanttoacknowledgeanumberofcaveats.Thereisnodirectevidenceinthesecancersthattumorigeniccellsdifferfromnontumorigeniccellsasaresultofepigeneticratherthangeneticdifferences.Moreover,theconclusionthattransplantedcancerstemcellsHeterogeneityinCancer:CancerStemCellsversusClonalEvolutionMarkShackleton,1ElsaQuintana,1EricR.Fearon,2andSeanJ.Morrison1,2,*1HowardHughesMedicalInstitute,LifeSciencesInstitute,CenterforStemCellBiology2DepartmentofInternalMedicineUniversityofMichigan,AnnArbor,MI48109,USA*Correspondence:seanjm@https://www.sodocs.net/doc/7d9770465.htmlDOI10.1016/j.cell.2022.08.017Theidentificationandcharacterizationofcancerstemcellsmightleadtomoreeffectivetreat-mentsforsomecancersbyfocusingtherapyonthemostmalignantcells.Toachievethisgoalitwillbenecessarytodeterminewhichcancersfollowacancerstemcellmodelandwhichdonot,toaddresstechnicalissuesrelatedtotumorigenesisassays,andtotesttheextenttowhichcancercellheterogeneityarisesfromgeneticversusepigeneticdifferences.本文来源：网络收集与整理，如有侵权，请联系作者删除，谢谢！