cancer stem cells3

8/8/2019 Cancer Stem Cells3

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STEM CELLS IN SOLIDSTEM CELLS IN SOLIDTUMORSTUMORS

CANCER STEM CELLCANCER STEM CELL

(CSC)(CSC)


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Whatare stem cells?Whatare stem cells?

**** StemStem cellscells areare unspecializedunspecialized immatureimmature cellscells thatthat cancan renewrenewthemselvesthemselves throughthrough cellcell divisiondivision forfor longlong periodsperiods ofof timetime..

**** TheyThey areare necessarynecessary forfor ourour survivalsurvival.. SkinSkin stemstem cellscells renewrenewandand repairrepair ourour skinskin.. CellsCells inin ourour bonebone marrowmarrow generategenerate thethedifferentdifferent cellcell typestypes inin ourour bloodblood..

**** UnderUnder specificspecific conditions,conditions, physiologicalphysiological oror experimental,experimental,stemstem cellscells cancan differentiatedifferentiate alongalong distinctdistinct lineageslineages throughthroughsystemicsystemic differentiationdifferentiation stepssteps generatinggenerating progenitorsprogenitors toto thethefinalfinal stagestage ofof differentiationdifferentiation:: MuscleMuscle cells,cells, nervenerve cells,cells, bonebonecellscells etcetc

**** TheThe bloodblood systemsystem hashas thethe bestbest describeddescribed normalnormal stemstem

cellscells..


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Types of stem cellsTypes of stem cells

EmbryonicEmbryonic stemstem cellscells (pluripotent)(pluripotent)::

**** TheyThey havehave thethe potentialpotential toto generategenerate allall cellcelltypestypes inin anyany organorgan oror tissuetissue inin thethe bodybody

**** TheyThey comecome fromfrom aa blastocyst,blastocyst, aa smallsmall spheresphere ofofcellscells thatthat resultsresults fromfrom cellcell divisiondivision inin aa fertilizedfertilizedovumovum..

**** ForFor researchresearch purposes,purposes, cellscells areare harvestedharvested fromfromthethe innerinner cellcell massmass ofof thethe blastocystblastocyst whenwhen itit isisapproximatelyapproximately sixsix daysdays oldold andand consistsconsists ofofaroundaround 200200 cellscells


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Types of stem cellsTypes of stem cells

AdultAdult stemstem cellscells (multipotent(multipotent stemstem cells)cells)::

TheyThey areare postembryonicpostembryonic stemstem cellscells requiredrequired forfor normalnormalcellularcellular turnoverturnover andand repairrepair

TheThe bestbest exampleexample isis thethe hematopoietichematopoietic stemstem cellcell butbut theytheyareare foundfound inin nearlynearly everyevery majormajor organorgan

TheyThey areare relativelyrelatively undifferentiatedundifferentiated cellscells thatthat areare ableable

toto maintainmaintain theirtheir ownown numbersnumbers forfor lifelife throughthroughcontinuouscontinuous divisiondivision

TheirTheir progenyprogeny cancan differentiatedifferentiate intointo variousvarious cellcelllineageslineages

TheyThey dividedivide slowlyslowly andand thisthis reducesreduces thethe raterate atat whichwhich

stemstem cellscells acquireacquire DNA

DNA

mutationsmutations


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How can stem cells be usedtoHow can stem cells be usedto

treatdiseases?treatdiseases?

Stem cells as REPLACEMENT PARTS:Stem cells as REPLACEMENT PARTS:

AA widewide rangerange ofof diseasesdiseases (heart(heart disease,disease,

Parkinsons,Parkinsons, Alzheimers,Alzheimers, diabetes,diabetes, motormotor

neuronneuron disease,disease, etcetc..)) maymay bebe amenableamenable toto stemstem

cellcell therapytherapy.. StemStem cellscells werewere directeddirected toto thethe

appropriateappropriate placeplace inin thethe bodybody andand becomebecome thethe

appropriateappropriate cellcell typetype..

ExEx.. stemstem cellscells couldcould bebe mademade toto migratemigrate toto anan

injuredinjured spinalspinal cordcord andand becomebecome nervenerve cellscells toto

curecure paralysisparalysis


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How can stem cells be usedtoHow can stem cells be usedto

treatdiseases?treatdiseases?22) Developingdrugtherapies:) Developingdrugtherapies:

ItIt isis possiblepossible toto makemake stemstem cellscells thatthat arearegeneticallygenetically identicalidentical toto thosethose ofof aa patientpatient withwith aadiseasedisease..

TheThe stemstem cellscells cancan bebe mademade toto generategenerate thethe cellcelltypetype thatthat isis defectivedefective inin thatthat diseasedisease..

ByBy studyingstudying thesethese cells,cells, wewe cancan gaingain insightinsight intointowhatwhat goesgoes wrongwrong atat thethe molecularmolecular levellevel inin thethediseasedisease..

WeWe cancan alsoalso useuse thesethese cellscells toto testtest drugsdrugs thatthat

mightmight blockblock thethe progressionprogression ofof thethe diseasedisease


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Cancer stem celltheoryCancer stem celltheory

TheThe ideaidea ofof cancercancer cellscells arisingarising fromfrom aa

commoncommon originorigin hashas beenbeen thoroughlythoroughly

explainedexplained andand publishedpublished asas thethe UnitarianUnitarian ororTrophoblasticTrophoblastic theorytheory ofof cancercancer inin 19501950..

ItIt statesstates thatthat cancercancer----differentiateddifferentiated

trophoblasttrophoblast proliferationproliferation---- isis partpart ofof thethe

healinghealing process,process, andand thethe diseasedisease onlyonly

manifestsmanifests ifif itsits controlcontrol ((immuneimmune responseresponse andand

nutritionnutrition)) areare impededimpeded..


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There are two competing visions ofThere are two competing visions oftumors.tumors.

Old cancer model:Old cancer model:11)) AllAll tumortumor cellscells cancan formform newnew tumorstumors andand areare

thereforetherefore equallyequally tumorigenictumorigenic..

22)) UnregulatedUnregulated growthgrowth isis duedue toto serialserial acquisitionacquisition

ofof geneticgenetic eventsevents leadingleading toto thethe expressionexpression ofofgenesgenes thatthat promotepromote cellcell proliferationproliferation withwithconcomitantconcomitant silencingsilencing ofof growthgrowth inhibitoryinhibitorygenesgenes andand bluntingblunting ofof cellcell deathdeath..

33)) CancerCancer isis aa proliferativeproliferative diseasedisease..


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New cancer model:New cancer model:11)) TumorsTumors arisearise fromfrom cellscells termedtermed cancercancer stemstem cellscells thatthat

havehave propertiesproperties ofof normalnormal stemstem cells,cells, particularlyparticularly selfself--renewalrenewal andand multipotentialitymultipotentiality (a(a minority)minority) ofof tumortumorcellscells..

22)) UnregulatedUnregulated cellcell growthgrowth isis duedue toto aa disruptiondisruption inin thethe

regulatoryregulatory mechanismmechanism inin stemstem cellcell renewalrenewal..

33)) CancerCancer isis aa stemstem cellcell disorderdisorder andand notnot aa simplesimplemechanismmechanism wherebywhereby cellcell proliferationproliferation isis disrupteddisrupted..


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TheseThese CSCsCSCs cellscells persistpersist inin tumorstumors asas aa

distinctdistinct populationpopulation thatthat likelylikely causescauses

relapsesrelapses andand metastasismetastasis..

ThisThis theorytheory explainsexplains whywhy areare manymany

cancerscancers soso difficultdifficult toto treattreat..


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Why stem cells?Why stem cells?

OnlyOnly stemstem cellscells havehave thethe abilityability toto selfself renewrenew

andand neoplasianeoplasia isis essentiallyessentially dysregulateddysregulated selfself

renewalrenewal

StemStem cellscells areare longlong--livedlived cellscells whichwhich cancanacquireacquire thethe necessarynecessary numbernumber ofof sequentialsequential

mutationsmutations toto convertconvert aa normalnormal cellcell intointo aa

malignantmalignant oneone..


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Are wetargetingtherightAre wetargetingtheright

cells?cells?

ConventionalConventional chemotherapieschemotherapies killkill differentiateddifferentiated orordifferentiatingdifferentiating cells,cells, whichwhich formform thethe bulkbulk ofof thethe tumortumor butbut

areare unableunable toto generategenerate aa newnew oneone..

AA populationpopulation ofof CSCs,CSCs, whichwhich gavegave riserise toto it,it, remainsremainsuntoucheduntouched andand maymay causecause aa relapserelapse ofof thethe diseasedisease..

DevelopmentDevelopment ofof specificspecific therapiestherapies targetedtargeted atat CSCsCSCs holdsholdshopehope forfor improvementimprovement ofof survivalsurvival andand qualityquality ofof lifelife ofofcancercancer patients,patients, especiallyespecially forfor suffererssufferers ofof metastaticmetastaticdiseasedisease,, wherewhere littlelittle progressprogress hashas beenbeen mademade inin recentrecentyearsyears..


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WRONG TARGET. Traditional cancer therapies (top) kill rapidly dividing tumor

cells (blue) but may spare stem cells (yellow) that can give rise to a new tumor. In

theory, killing cancer stem cells (bottom) should halt a tumor's growth lead to its

disappearance.


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Whatare Cancer StemWhatare Cancer Stem

Cells?Cells?CellsCells thatthat havehave propertiesproperties ofof normalnormal stemstem cellscells::

11)) TheThe abilitiesabilities toto selfself--renewrenew..

22)) ThaTha abilityability toto differentiatedifferentiate intointo multiplemultiple cellcell

typestypes..

33)) TheyThey formform aa distinctdistinct populationpopulation inin tumorstumors

thatthat likelylikely causescauses diseasedisease relapserelapse andandmetastasismetastasis..


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SelfSelf--renewal of stem cellsrenewal of stem cells

TheThe conceptconcept ofof selfself--

renewalrenewal isis crucialcrucial toto

understandunderstand CSC,CSC, andandalsoalso toto getget insightinsight onon thethe

mechanismmechanism byby whichwhich

currentcurrent therapiestherapies mightmight

evadeevade thethe availableavailabletreatmentstreatments..


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SelfSelf--renewal of stem cellsrenewal of stem cells

1)1) ProvidesProvides thethe cellcell withwith thethe abilityability toto undergoundergo infiniteinfinitecellularcellular divisionsdivisions withwith onlyonly fewfew ofof thethe stemstem cellscellsdividingdividing atat aa particularparticular timetime..

22)) TheThe doublingdoubling timetime ofof mostmost stemstem cellscells isis relativelyrelatively longlong,, asascomparedcompared toto theirtheir immediateimmediate progenitors,progenitors, whichwhichreplicatereplicate withwith shortershorter doublingdoubling timestimes (Repair(Repair ofof DNADNAdamage)damage)..

33)) InIn somesome stemstem cellscells atat divisiondivision thethe `mother`mother cellcell retainretain thetheoriginaloriginal chromosomechromosome whilewhile providingproviding thethe daughterdaughterwithwith thethe newlynewly formedformed chromosomechromosome (Chromosomal(Chromosomal

preservation)preservation) minimizesminimizes mutationmutation inin thethe mothermother

cellcell..


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CSC DevelopmentCSC Development

TheThe molecularmolecular pathwayspathways forfor stemstemcellcell differentiationdifferentiation areare complexcomplex

indicatingindicating thatthat dysregulationdysregulation couldcouldoccuroccur atat multiplemultiple sitessites toto turnturn offoffthethe homeostatichomeostatic balancebalance andand createcreate

abnormalabnormal cells,cells, oror cancercancer cells,cells, alsoalsoreferredreferred asas malignantmalignant cellscells orortransformedtransformed cellscells..


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Normal Stem Cells vs. CancerNormal Stem Cells vs. Cancer

Stem CellsStem Cells

TheThe stemstem cellscells inin tumorstumors (CSCs)(CSCs) areare notnot thethe

samesame typetype ofof stemstem cellscells beingbeing exploredexplored asas

potentialpotential therapiestherapies toto treattreat degenerativedegenerative

diseasesdiseases..

ButBut theythey developdevelop becausebecause ofof mutationsmutations thatthataccumulateaccumulate overover yearsyears andand oftenoften decadesdecades.. TheThe

mutationsmutations areare thoughtthought toto promotepromote thethe tumortumor

stemstem cells'cells' abilityability toto proliferate,proliferate, eventuallyeventually

leadingleading toto cancercancer


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Evidence forthe presenceEvidence forthe presence

of CSCof CSC11)) InIn expexp.. AnimalAnimal research,research, efficientefficient tumortumor formationformation toto

establishestablish aa tumortumor.. ThisThis waswas formerlyformerly explainedexplained byby::

**** PoorPoor methodologymethodology (loos(loos ofof cellcell viabilityviability duringduringtransfer)transfer)..

**** TheThe criticalcritical importanceimportance ofof thethe microenvironmentmicroenvironment..**** TheThe particularparticular biochemicalbiochemical surroundingssurroundings ofof thetheinjectedinjected cellscells..

AccordingAccording toto CSCCSC theorytheoryonlyonly aa smallsmall fractionfraction ofof thethe injectedinjected cells,cells, thethe CSCCSC,, havehavethethe potentialpotential toto generategenerate aa tumortumor.. InIn humanhuman AMLAML thethefrequencyfrequency ofof thesethese cellscells isis lessless thanthan 11 inin 1010,,000000..


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Evidence for cancer stemEvidence for cancer stem

cellscells22)) TumorTumor heterogeneityheterogeneity:: MostMost umorsumors areare

veryvery heterogeneousheterogeneous andand heterogeneityheterogeneity isis

commonlycommonly retainedretained byby tumortumor metastasesmetastases..

ThisThis impliesimplies thatthat thethe cellcell thatthat producedproduced

themthem hadhad thethe capacitycapacity toto generategenerate multiplemultiplecellcell typestypes ((havehave aa multidifferentiativemultidifferentiative

potentialpotential),), aa classicalclassical hallmarkhallmark ofof stemstem

cellscells..


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CSCCSC-- PATHWAYSPATHWAYS

AA normalnormal stemstem cellcell maymay bebe transformedtransformed intointo aa

cancercancer stemstem cellcell throughthrough disregulationdisregulation ofof thethe

proliferationproliferation andand differentiationdifferentiation pathwayspathwayscontrollingcontrolling itit..

TheThe firstfirst findingsfindings inin thisthis areaarea werewere mademade usingusing

haematopoietichaematopoietic stemstem cellscells (HSCs)(HSCs) andand theirtheir

transformedtransformed counterpartscounterparts inin leukemialeukemia..

However,However, thesethese pathwayspathways appearappear toto bebe sharedshared

byby stemstem cellscells ofof allall organsorgans..


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BmiBmi--11

ThisThis groupgroup ofof transcriptionaltranscriptional repressorrepressor

waswas discovereddiscovered asas aa commoncommon oncogeneoncogene

activatedactivated inin lymphomalymphoma andand laterlater shownshown toto

specificallyspecifically regulateregulate HSCsHSCs andand neuralneural

stemstem cellscells.. ThisThis pathwaypathway appearsappears toto bebeactiveactive inin CSCCSC ofof pediatricpediatric brainbrain tumorstumors

andand CRCCRC


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BmiBmi--11

**** InIn normalnormal cellscells BMIBMI--11 inhibitsinhibits thethe transcriptiontranscription ofofCDNKCDNK22AA whichwhich encodesencodes twotwo cyclincyclin dependentdependent kinasekinase

inhibitors,inhibitors, INKINK44AA andand ARFARF..

**** CellCell cyclecycle progressionprogression isis promotedpromoted inin thethe absenceabsence ofofINKINK44AA andand propro--apoptoticapoptotic genesgenes areare inhibitedinhibited inin thetheabsenceabsence ofofARFARF.. Hence,Hence, BMIBMI--11 promotespromotes proliferationproliferation

andand inhibitsinhibits apoptosisapoptosis..

**In**In thethe casecase ofof cancer,cancer, BMIBMI--11 isis circumventedcircumvented andandCDNKCDNK22AA isis nono longerlonger inhibited,inhibited, therebythereby resultingresulting ininunregulatedunregulated proliferationproliferation andand selfself--renewalrenewal..


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NotchNotch

TheThe NotchNotch pathwaypathway hashas beenbeen knownknown toto developmentaldevelopmentalbiologistsbiologists forfor decadesdecades..

ItsIts rolerole inin controlcontrol ofof stemstem cellcell proliferationproliferation hashas nownowbeenbeen demonstrateddemonstrated forfor severalseveral cellcell typestypes includingincludinghaematopoietic,haematopoietic, neuralneural andand mammarymammary stemstem cellscells..

ComponentsComponents ofof thethe NotchNotch pathwaypathway havehave beenbeen proposedproposedtoto actact asas oncogenesoncogenes inin mammarymammary andand otherother tumorstumors..


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Wnt/Wnt/--cateninecatenine

ThisThis pathwaypathway isis stronglystrongly implicatedimplicated asas stemstem cellcellregulatorsregulators..

ItIt isis commonlycommonly hyperactivatedhyperactivated inin tumorstumors andand isisrequiredrequired toto sustainsustain tumortumor growthgrowth..

TheirTheir rolerole hashas beenbeen illustratedillustrated especiallyespecially inin gliomasgliomas (the(theGliGli transcriptiontranscription factors),factors), CRCCRC andand mammarymammary tumorstumors..


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TheWntTheWnt--BB--cateninecatenine

pathwaypathway InIn thethe normalnormal WntWnt pathwaypathway thethe levelslevels ofof thethe

transcriptiontranscription factorfactor --catenincatenin mediatesmediates selfself--renewalrenewal..

--catenincatenin couldcould bebe turnedturned offoff byby aa destructiondestructioncomplexcomplex asas aa feedbackfeedback mechanismmechanism..

However,However, inin cancercancer thethe controlcontrol processprocess isiscircumventedcircumvented andand --catenincatenin levelslevels constantlyconstantlythrive,thrive, hencehence causingcausing continualcontinual proliferationproliferationandand selfself-- renewalrenewal..


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TheWntTheWnt--BB--catenine pathwaycatenine pathway


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CSCs indifferent solidCSCs indifferent solid

tumorstumorsStem cells may cause some forms of boneStem cells may cause some forms of bone cancer,cancer, University ofUniversity of

FloridaFlorida

OsteosarcomaOsteosarcoma occursoccurs rightright nextnext toto thethe mostmost activeactive centerscenters ofof growth,growth,

thethe growthgrowth platesplates inin longlong bonesbones..

TheseThese areasareas ofof thethe skeletonskeleton containcontain manymany stemstem cellscells undergoingundergoing rapidrapidgrowthgrowth andand developingdeveloping intointo bonebone duringduring thethe adolescentadolescent growthgrowth spurtspurt..

AA stimulated,stimulated, abnormalabnormal stemstem cellcell mightmight thereforetherefore bebe thethe cellcell ofof originorigin ofofosteosarcomaosteosarcoma..

stemstem--likelike cellscells werewere isolatedisolated fromfrom tumorstumors.. AboutAbout oneone inin 11,,000000 cellscells ininthethe samplessamples hadhad featuresfeatures ofof embryonicembryonic stemstem cellscells.. TheThe researchersresearchers alsoalsofoundfound abundantabundant levelslevels ofof thethe twotwo keykey factorsfactors thatthat helphelp maintainmaintainembryonicembryonic stemstem cellscells inin aa veryvery primitiveprimitive statestate..


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The Real Problemin BreastThe Real Problemin Breast

Tumors: Cancer Stem CellsTumors: Cancer Stem Cells

AtAt thethe UniversityUniversity ofof

MichiganMichigan researchersresearchers havehave

identifiedidentified aa smallsmall populationpopulationofof cellscells inin breastbreast tumorstumors thatthat

cancan seedseed thethe growthgrowth ofof newnew

cancerscancers.. TheseThese cancercancer--

causingcausing cells,cells, whichwhich makemake upup

aa tinytiny fractionfraction ofof cellscells withinwithin

tumors,tumors, havehave propertiesproperties

similarsimilar toto thosethose ofof stemstem cellscells..


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CSCs in ColorectalCSCs in Colorectal

carcinomacarcinoma


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CSCs in ColorectalCSCs in Colorectal

carcinomacarcinoma


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CSCs inHepatocellularCSCs inHepatocellular

carcinomacarcinoma


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CSC hypothesis & DrugCSC hypothesis & Drug

ResistanceResistance TheThe CSCCSC hypothesishypothesis statesstates:: thethe cancercancer--initiatinginitiating cellcell

isis aa transformedtransformed tissuetissue stemstem cell,cell, whichwhich retainsretains thetheessentialessential propertyproperty ofof selfself--protectionprotection throughthrough thethe

activityactivity ofof multiplemultiple drugdrug resistanceresistance transporterstransporters..

ThisThis restingresting constitutivelyconstitutively drugdrug--resistantresistant cellcell remainsremainsatat lowlow frequencyfrequency amongamong aa heterogeneousheterogeneous tumortumor massmass..

TheThe mutationmutation allowsallows forfor unbridledunbridled cellcell growthgrowth andandresistanceresistance toto chemotherapeuticchemotherapeutic effortsefforts sincesince CSCsCSCsexpressexpress genesgenes forfor drugdrug resistanceresistance andand antianti--apoptoticapoptoticmechanism,mechanism, ..


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CONCLUSIONCONCLUSION

StemStem cellscells areare immatureimmature cellscells thatthat cancan replicate,replicate, oror

renewrenew themselves,themselves, andand areare ableable toto differentiatedifferentiate intointo

allall cellscells typestypes..

mutationsmutations andand rearrangementsrearrangements ofof thethe genomesgenomes ofof

stemstem cellscells givegive riserise toto CSCsCSCs.. TheseThese changeschanges couldcould

underlieunderlie thethe developmentdevelopment ofof cancerscancers inin manymany tissuestissues..

StemStem cellscells areare moremore difficultdifficult toto killkill.. BecauseBecause theythey arearesoso importantimportant throughoutthroughout aa person'sperson's lifetime,lifetime, theythey

havehave developeddeveloped mechanismsmechanisms thatthat protectprotect themselvesthemselves..

Therefore,Therefore, tumortumor stemstem cellscells areare ableable toto resistresist toxictoxic

substances,substances, suchsuch asas cancercancer drugsdrugs..


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CONCLUSIONCONCLUSION

TheThe nextnext stepstep isis toto figurefigure outout whatwhat makesmakes thethe CSCCSCdifferentdifferent fromfrom thethe otherother cellscells inin thethe tumortumor..

DNADNA microarraysmicroarrays couldcould bebe usedused toto identifyidentify genesgenesthatthat areare activeactive inin thethe cancercancer--causingcausing cellscells (CSCs)(CSCs)comparedcompared toto otherother tumortumor cellscells.. SomeSome ofof thesethese genesgenesmightmight controlcontrol thethe cell'scell's abilityability toto replicatereplicate andandmetastasizemetastasize..

IdentifyingIdentifying thesethese genesgenes maymay suggestsuggest newnew drugdrug targetstargetsthatthat couldcould selectivelyselectively killkill thethe cancercancer cellscells

cancer stem cells3

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