Cancer stem cells and cancer therapy

REVIEWCancerstemcellsandcancertherapySaraSoltanian&MaryamM.MatinReceived:1November2010/Accepted:10January2011/Publishedonline:12February2011#InternationalSocietyofOncologyandBioMarkers(ISOBM)2011AbstractCancerstemcells(CSCs)areasubpopulationoftumourcellsthatpossessthestemcellpropertiesofself-renewalanddifferentiation.Stemcellsmightbethetargetcellsresponsibleformalignanttransformation,andtumourformationmaybeadisorderofstemcellself-renewalpathway.Epigeneticalterationsandmutationsofgenesinvolvedinsignaltransmissionsmaypromotetheforma-tionofCSCs.Thesecellshavebeenidentifiedinmanysolidtumoursincludingbreast,brain,lung,prostate,testis,ovary,colon,skin,liver,andalsoinacutemyeloidleukaemia.TheCSCtheoryclarifiesnotonlytheissueoftumourinitiation,development,metastasisandrelapse,butalsotheineffectivenessofconventionalcancertherapies.Treatmentsdirectedagainstthebulkofthecancercellsmayproducestrikingresponsesbuttheyareunlikelytoresultinlong-termremissionsiftherareCSCsarenottargeted.Inthisreview,weconsiderthepropertiesofCSCsandpossiblestrategiesforcontrollingtheviabilityandtumour-igenecityofthesecells,includingtherapeuticmodelsforselectiveeliminationofCSCsandinductionoftheirproperdifferentiation.KeywordsCancerstemcell.Tumour.Differentiationtherapy.EliminationtherapyIntroductionThetraditionalmodelofcancerdevelopmentsuggeststhattumoursarisefromaseriesofsequentialmutationsresultingfromgeneticinstabilityand/orenvironmentalfactorsaffectingnormalcells.Accordingtothismodel,manycancercellshavebeenconsideredtohavetumourigenicpotential.Amajorhurdleforthetraditionalmodelofcancerdevelopmentistheprolongedperiodrequiredtodevelopthefirstmutationthatsubsequentlyleadstomalignanttumourformation.Inmanytissuesinwhichtumoursarise(e.g.gastrointestinaltract,epithelium,skinandblood),maturecellshaveashortlifespanandalimitedopportunitytoaccumulatethemultiplemutationsrequiredfortumourdevelopment[1,2].Therefore,theprobabilityofanindividualcellaccumulatingthenecessarymutationsissmall.Analternativeexplanationthathasbeenproposedisthestemcellmodeloftumourformation.Accordingtothismodel,tumoursoriginateineitherlong-livedtissuestemcellsorprogenitorcellsthroughmisregulationofthenormallytightlyregulatedprocessofself-renewal,leadingtocancerstemcells(CSCs)[1,3,4].OtherterminologiesforCSCsaretumour-initiatingcells(TICs)andtumourigeniccancercells.AhypothesisofCSCsstatingthattheyhavesimilarpropertiestostemcellswasfirstexplainedbyRudolfVirchowandJuliusConheiminthenineteenthcentury.Virchow’sembryonal-resthypothesisstatesthatcancersarisefromactivationofdormantcells(whichareremaindersofembryoniccells)presentinadulttissues.Thishypothesiswasbasedonthefactthattherearesomesimilaritiesbetweendevelopingembryoniccellsandsomecancercellsincludingtheirabilitytoproliferateanddifferentiate[5,6].Accordingtocancerstemcellmodelandbasedonexperimentsinwhichhumancancercellswerexenotrans-plantedintonon-obesediabetic/severe-combinedimmuno-S.Soltanian:M.M.Matin(*)DepartmentofBiology,FacultyofScience,FerdowsiUniversityofMashhad,Mashhad,Irane-mail:[e-mail]earchGroup,InstituteofBiotechnology,FerdowsiUniversityofMashhad,Mashhad,IranTumorBiol.(2011)32:425–440DOI10.1007/s13277-011-0155-8deficient(NOD/SCID)mice(thathaveadefectinTcells,Bcells,naturalkillercells,andcomplement),onlysmallsubpopulationsofcancercellsretainedthecapacitytoinitiate,maintainandpromotethedevelopmentofthetumours[7–17].Althoughxenotransplantationanimalmodelshaveimprovedthepossibilitytostudythecancerstemcellhypothesis,thecriticalroleoftumourgrowthanditsinteractionswiththelocalandextendedmicroenviron-mentcomplicatestheinterpretationofsuchstudies.Thelowfrequencyoftumour-producingcellsfrom,forexam-ple,humanacutemyeloidleukaemia(AML)inNOD/SCIDmicemightbeexplainedbythefactthatraretumourcellshavebeenabletoadapttoaforeignenvironmentandcontinuetogrow[18].Modificationstothexenotransplan-tationassayhaverevealedthatmanymorehumancellshavetumourigenicpotentialcomparedtotheresultsobtainedinNOD/SCIDmice.Forexample,Quintanaetal.,showedthatmelanoma-initiatingcellsarerareinNOD/SCIDmice,butmoremelanoma-initiatingcellscouldbedetectedinNOD/SCIDmicelackingtheinterleukin-2gammareceptor(NSG,NODscidgamma)owinginparttothelackofnatural-killercellactivityinNSGmice.Therefore,moretumourigeniccellscouldbedetectedinNSGmice,whicharemoreimmunodeficientthanNOD/SCIDmice[19].Additionalmodificationstoxenotrans-plantationassayssuchasco-injectionoftumourcellswithMatrigel(gelmediumcontaininggrowthfactorsandnutrientsthatcouldreinforcethetumourcells’vitality)andincreasingthelengthofobservationfortumourformationshowthatfrequencyofTICsincreasesdramati-callyviamorepermissivexenotransplantation[13,19].Thesedataindicatethatsomecancers,whichappeartohaveraretumourigeniccellsinNOD/SCIDmice,actuallyhavemorecellswithtumourigeniccapacityunderotherconditions,raisingthepossibilitythatthetruefrequencyofCSCshasbeengreatlyunderestimatedinmosthumantumours.Nevertheless,othercancersmaystillhaveinfrequenttumourigeniccells,evenwhenstudiedunderoptimisedc