Cancer Development | CancerQuest

Substances that can cause cancer are known as carcinogens. The process of cancer development is called carcinogenesis. Certain carcinogenic chemicals are ... Skiptomaincontent Selectyourlanguage EnglishEspañol简体中文 Providingreliableinformationaboutcancerbiologyandtreatment Mainnavigation TestYourKnowledgewiththe"CancerDevelopment"SectionQuiz TableofContents IntroductionBelowisalistoftopicscoveredinthissection:StagesofTumorDevelopmentTheSearchforCancerStemCellsWhatledtothesearchforcancerstemcells?CancerStemCellsandTreatment × LearnHowTheCoronavirusandCOVID-19ImpactsCancer Patients ViewPDF CancerDevelopment ​ Introduction Simplyput,canceristheresultofunregulatedcelldivision.Cancercellsdividewhentheyarenotsupposedto,don'tstopdividingwhentheyaresupposedtoanddon'tdiewhentheyshould.Intheworstcases,thecancercellsleavetheareainwhichtheyaroseandtraveltootherpartsofthebody. Cancercellsdonotlookoractlikethenormalcellsfromwhichtheyoriginate.Itisreasonable,then,toask'Whydocancercellsbehavesobadly?'.Itturnsouttheanswerslieinthegenesoftheaffectedcells.Incancercells,changestokeygenescausethecellstoactabnormally.ThechangesareoftentheresultofchangestotheDNA(mutations)inthecells.Becausetherearemanydifferentthingsthatarecapableofcausingmutation,thereareanequallylargenumberofcausesofcancer. Thedevelopmentofcancertakesplaceinamulti-stepprocess.Asthecellsbecomemoreabnormal,theygainnewcapabilities,suchastheabilitytoreleasegrowthfactorsanddigestiveenzymes.Thecellscontinuetodivide,impactingnearbynormalcells,oftenreducingthefunctionoftheaffectedorgan.Evenabnormalcancercellsdiesometimesandatumorthatislargeenoughtofeelcantakeyearstoreachthatsize.Althoughnotallcancersshareexactlythesamesteps,therearesome generalfeaturesthataresharedinthedevelopmentofmanytypesofcancer. FurtherinformationonthetopicsonthispagecanalsobefoundinmostintroductoryBiologytextbooks,werecommendCampbellBiology,11thedition.1 Belowisalistoftopicscoveredinthissection: CancerInitiation,PromotionandProgression StagesofTumorDevelopment CancerStemCells TheSearchforCancerStemCells CancerStemCellsandTreatment SectionSummary CancerInitiation,Promotion,andProgression Intheeighteenthcentury,LondonphysicianPercivalPottmadethefirstlinkbetweencancerandenvironmentalagentswhenhenotedahighincidenceofscrotalcanceramongchimneysweeps.Hehypothesizedthatitwascausedbyexposuretocoalsandtars.Outofthisobservationgrewthetwo-stagemodelofcancerdevelopmentby1)initiatorsand2)promoters.IntheyearssincePott'sobservationsawiderangeofchemicals,radiationsources,virusesandbacteriahavebeenimplicatedinthedevelopmentofcancer.2 Theinitialexperimentalstudiesofcarcinogenesiswereconductedinanimals.ChemicalsabletoreactwithDNAandnon-reactivecompoundswerebothtestedfortheirabilitytocausecancer.Themodelusedwasmouseskincarcinogenesis.Inthissystemresearcherspaintedtestchemicalsontheskinandobservedthegrowthoftumors.ResearchersfoundthatapplicationofaDNAreactivesubstanceonlyresultedintumorformationwhentheanimalswerefurthertreatedwithanothernon-reactivesubstance.AcompoundthatreactswithDNAandsomehowchangesthegeneticmakeupofthecelliscalledamutagen.Themutagensthatpredisposecellstodeveloptumorsarecalledinitiatorsandthenon-reactivecompoundsthatstimulatetumordevelopmentarecalledpromoters.Approximately70%ofknownmutagensarealsocarcinogens--cancer-causingcompounds.3 Acompoundthatactsasbothaninitiatorandapromoterisreferredtoasa'completecarcinogen'becausetumordevelopmentcanoccurwithouttheapplicationofanothercompound.4 Initiation Initiationisthefirststepinthetwo-stagemodelofcancerdevelopment.Initiators,ifnotalreadyreactivewithDNA,arealtered(frequentlytheyaremadeelectrophilic)viadrug-metabolizingenzymesinthebodyandarethenabletocausechangesinDNA(mutations).4 Sincemanyinitiatorsmustbemetabolizedbeforebecomingactive,initiatorsareoftenspecifictoparticulartissuetypesorspecies.5 Theeffectsofinitiatorsareirreversible;onceaparticularcellhasbeenaffectedbyaninitiatoritissusceptibletopromotionuntilitsdeath.Sinceinitiationistheresultofpermanentgeneticchange,anydaughtercellsproducedfromthedivisionofthemutatedcellwillalsocarrythemutation.4 Instudiesofmouseskincarcinogenesis,alinearrelationshiphasbeenobservedbetweenthedoseofinitiatorandthequantityoftumorsthatcanbeproduced,thusanyexposuretotheinitiatorincreasesriskandthisriskincreasesindefinitelywithhigherlevelsofexposure.5 Promotion Onceacellhasbeenmutatedbyaninitiator,itissusceptibletotheeffectsofpromoters.Thesecompoundspromotetheproliferationofthecell,givingrisetoalargenumberofdaughtercellscontainingthemutationcreatedbytheinitiator.6 Promotershavenoeffectwhentheorganisminquestionhasnotbeenpreviouslytreatedwithaninitiator.5 Unlikeinitiators,promotersdonotcovalentlybindtoDNAormacromoleculeswithinthecell.Manybindtoreceptorsonthecellsurfaceinordertoaffectintracellularpathwaysthatleadtoincreasedcellproliferation.4 Therearetwogeneralcategoriesofpromoters:specificpromotersthatinteractwithreceptorsonorintargetcellsofdefinedtissuesandnonspecificpromotersthataltergeneexpressionwithoutthepresenceofaknownreceptor.Promotersareoftenspecificforaparticulartissueorspeciesduetotheirinteractionwithreceptorsthatarepresentindifferentamountsindifferenttissuetypes. Whiletheriskoftumorgrowthwithpromoterapplicationisdose-dependent,thereisbothathresholdandamaximumeffectofpromoters.Verylowdosesofpromoterswillnotleadtotumordevelopmentandextremelyhighdoseswillnotproducemoreriskthanmoderatelevelsofexposure.5 Progression Inmice,repeatedpromoterapplicationsoninitiator-exposedskinproducesbenignpapillomas.Mostofthesepapillomasregressaftertreatmentisstopped,butsomeprogresstocancer.Thefrequencyofprogressionsuggeststhatthepapillomasthatprogresstocancerhaveacquiredanadditional,spontaneous,mutation.7 Thetermprogression,coinedbyLeslieFoulds,referstothestepwisetransformationofabenigntumortoaneoplasmandtomalignancy.Progressionisassociatedwithakaryotypicchangesincevirtuallyalltumorsthatadvanceareaneuploid(havethewrongnumberofchromosomes).Thiskaryotypicchangeiscoupledwithanincreasedgrowthrate,invasiveness,metastasisandanalterationinbiochemistryandmorphology.5 StagesofTumorDevelopment Thegrowthofatumorfromasingle geneticallyalteredcellisastepwiseprogression.Theprocessdescribedbelowisapplicableforasolidtumorsuchasacarcinomaorasarcoma.Bloodcelltumorsgothroughasimilarprocessbutsincethecellsfloatfreely,theyarenotlimitedtoonelocationinthebody. Hyperplasia-Thealteredcelldividesinanuncontrolledmannerleadingtoanexcessofcellsinthatregionofthetissue.Thecellshaveanormalappearancebuttherearetoomanyofthem! Dysplasia-Additionalgeneticchangesinthehyperplasticcellsleadtoincreasinglyabnormalgrowth.Thecellsandthetissuenolongerlooknormal.Thecellsandthetissuemaybecomedisorganized. Carcinomain situ-Additionalchangesmakethecellsandtissuesappearevenmoreabnormal.Thecellsarenowspreadoveralargerareaandtheregionofthetissueinvolvedprimarilycontainsalteredcells.Thecellsoften'regress'orbecomemoreprimitiveintheircapabilities.Anexamplewouldbealivercellthatnolongermakesliver-specificproteins.Cellsofthistypearesaidtobede-differentiatedoranaplastic.Akeyfacetofin situgrowthsisthatthecellsarecontainedwithintheinitiallocationandhavenotyetcrossedthebasal laminatoinvadeothertissues.Cancersofthistypeareoftentotallycurablebysurgerysincetheabnormalcellsareallinonelocation. Tumorsofthistypehavenotyetinvadedneighboringtissue.Basedoninformationaboutpatientswithsimilargrowthsandmicroscopicexamination,thesegrowthsareoftenconsideredtohavethepotentialtobecomeinvasiveandaretreatedasmalignantgrowths. Cancer(Malignanttumors)-Thesetumorshavetheabilitytoinvadesurroundingtissuesand/orspread(metastasize)toareasoutsidethelocaltissue.Thesemetastatictumorsarethemostdangerousandaccountforalargepercentageofcancerdeaths.Thenextfewsectionswillgointosomedetailonthechangesandcapabilitiesthatallowcancercellstoformlargetumorsandtometastasizetootherpartsofthebody. Sometumorsdonotprogresstothepointwheretheyinvadedistanttissues.Suchtumorsaresaidtobebenign.Becausetheydonotspreadbeyondtheirinitiallocation,theyarenotconsideredtobecancerous.Benigntumorsarelessoftenlethalthanmalignanttumors,buttheycanstillcauseserioushealthproblems.Largebenigntumorscanputpressureonorgansandcauseotherproblems.Inthecaseofbraintumors,thelimitedspacewithintheskullmeansthatalargegrowthinthebraincavitycanbefatal. MoreinformationonthistopicmaybefoundinChapters13and14ofTheBiologyofCancerbyRobertA.Weinberg. CancerStemCells Whatisastemcell? Astemcellisaspecialcelltypethathasboththeabilitytoreproduceexactcopiesofitself(alsocalledself-renewal)andtheabilitytochange(differentiate)intooneofthemanyspecializedcelltypesinthebody.Examplesofspecializedcellsthatarisefromstemcellsincludenerves,musclesandthecellsliningourdigestivesystem. Inmostpartsofthebody,stemcellsarenotveryactive.Insomelocations,includingthegastrointestinaltract,stemcellsdivideanddifferentiateconstantlytoreplacecellsthatareshedordie.Stemcellsalsoplayaroleinhealing damagedtissue. Belowisavideooftheprocessbywhichstemcellscanaccomplishbothself-renewalanddifferentiation.Theprocessiscalled"asymmetriccelldivision,"anditassuresthatstemcellsarealwaysavailablewhenneeded.8   YourbrowserdoesnotsupportHTML5embeddedvideo. Whatisacancerstemcell? Cancerstemcells(CSCs)arethoughttoarisefromnormalstemcells.Sometimes,geneticchangesormutationsdamagenormalstemcells, preventingthem functioningproperly.Ifthisimproperfunctionincludesuncontrolledreproduction,thenthenormalstemcellhastheabilitytoformatumor;itisnow acancerstemcell.  TheexistenceofCSCswaspredicteddecadesago,butrecentresearchhasidentifiedcancerstemcellsinmultiplecancertypes,promptingextensive researchinthisfield.8 9 Wheredocancerstemcellscomefrom? Intheory,CSCscouldbeformedinmorethanoneway.Mutationscouldoccurinadifferentiatedcell(i.e.askincell)causingthecelltogobackwardsor'devolve'intoacellwithsomestemcellabilities.Cancerstemcellscouldalsobeformedbythemutationofanormalstemcellthatcausesittobecomecancerous.Cancerstemcellshavebeencreatedinresearchlaboratoriesfromskincells10 Theresearchersusedavirustoactivatespecificpathwaysandgivethetargetcellstemcell-likequalities.Theresearchprovesthatanormalcellcanbecomeastemcellwiththerightsetofmutations. Theprobabilityofanyparticularcelldevelopingasetofmutationsthatleadstocancerisrelativelylow.Thecellstypesthatareaffectedbythemajorityofcancers,epithelialcells,haveshortlivesandareevenlesslikelytoaccumulateallthemutationstheyneed.Normalstemcells,whicharelong-lived,aremorelikelytobearoundlongenoughtoaccumulatethenecessarymutationsandareagoodpossiblesourceofcancerstemcells.8 Whatisthedifferencebetweenthecancerstemcellhypothesisoftheoriginofcancerandtraditionalviewsontheoriginofcancer? Thecancerstemcellhypothesissuggeststhatonlyasmallportionofcellsarecapableofbecomingcancerous.Inotherwords,onlyasmallpopulationofcellsinatumorisresponsibleforthecontinuous,uncontrolledgrowthseenincancer. Thetraditionalviewsontheoriginofcancerpredictthatanycellisabletoacquiremutationsthatleadtouncontrolledreproduction.Likewise,allofthecellsinatumorwouldbepredictedtobeabletodivideendlessly.9   TheSearchforCancerStemCells Whatledtothesearchforcancerstemcells? Thereareseveralreasonswhymanyresearchersfindthecancerstemcellhypothesisappealing.Cancerstemcellsprovideonepossibleexplanationforthefrequentfailureofcancertreatments,thelargeamountofcellsneededtocausecancergrowthinmodelorganisms,andgapsinothertheoriesofcancerdevelopment.Alargechallengehasbeentheidentificationandisolationofcancerstemcells.Researchershaveidentifiedsomecellsurfaceproteins(alsocalledmarkers)foundoncancercellsthathavesomeimportantstemcellcapabilities.ThesemarkersincludeCD44,CD133,andALDH1.9 Oneofthepiecesofevidencethatfavorstheexistenceofcancerstemcellsisthefactthatwhenresearcherslookattumorstheyappeartocontainseveraldifferentiatedcelltypes.Thetraditionaltheoryonthedevelopmentofcancerisabletoexplainthis,butthelargenumberofmutationsnecessarytocreatethemixtureisunlikely.Anillustration,-iftumorsformfromasinglemutatedcellthetumorwouldonlycontaincellsofthattyperatherthancellsofmanytypes:   YourbrowserdoesnotsupportHTML5embeddedvideo. Ifmultiplecellsofdifferenttypesinthesameareahavemutationsthiswouldleadtoatumorofmixedcelltypes:   YourbrowserdoesnotsupportHTML5embeddedvideo. Cancerstemcellshavetheabilitytoproducecellsofmanydifferenttypescreatingthemixtureofcellsfoundinatumor:   YourbrowserdoesnotsupportHTML5embeddedvideo. Thepossibilityofastemcellbecomingacancerstemcellis,statistically,morelikelytohappenthanmultiplemutationsinmultiplecellsinthesameareainordertoproduceatumorwithmultiplecelltypes.11 9   CancerStemCellsandTreatment WhatistheimpactofCSCsontreatment? Currenttreatmentstargetcancerbecausethedrugsactoncellsthatareactivelydividing.Mostofthesedrugsfunctionbyinducingthedeath(viaapoptosis)ofthecancercells.Cancerstemcellscarrymutationsthatleadtocancer,buttheydonotnecessarilydividequickly.Thisrelativelyinactivestatewouldallowthemtoavoidtheeffectsofcancertreatmentswhichwouldexplainthealltoofrequentrecurrencesofcancers.CSCsalsoefficientlyrepairDNAdamageandavoidapoptosismakingthemhardtargetsfortoday'sdrugs.Thisevasionoftreatmentcouldbelikenedtoaweedinagarden.Cancerstemcellsareliketherootsoftheweedandthemajorityofthetumormassistheleavesandstemoftheweed.Removingthevisiblepartoftheweedappearstokillit,buttherootsundergroundsoonsproutanotherstemandtheweedliveson.12 WhyisitdifficulttotargetCSCs? TheproblemsencounteredwhenclinicianstreatcancerarealsoseenwhenpurifiedCSCsaretreatedwithanti-cancerdrugs.BecausenormalstemcellsandCSCsareverysimilar,itisdifficulttokillCSCsandleavenormalstemcellsunharmed.DrugresistanceisanothermajorobstacleintreatingbothcancerandCSCs.Stemcellstendtohavehighlevelsofparticularcellularpumps(i.e.themultipledrugresistanceprotein,MDR)thatareabletoejectcancerdrugsfromthecellsmakingthedrugsineffective.Stemcellsarealsohardertokillthannormalcellsbecausetheyhaveanabilitytoblockthesignalsthatdrugslikechemotherapycausetoleadtodeath(apoptosis).Anexcessofantiapoptoticproteinshelpsstemcellsavoidtheeffectsofcancertreatments.12 CanCSCsbetargetedwithtreatment? Cancerstemcellscancauseproblemswithcancertreatments,butresearchersaretryingtocomeupwithwaystotargetthem. Apotentialcancerdrug,napabucasin,hasbeenfoundtotarget'stemness.'Accordingtotwoseparatestudies,atreatmentcombiningnapabucasinwithchemotherapywasabletoblockSTAT3genetranscriptionincancerstemcells.13 Napabucasinwasshowntokillcolorectalstemcells,blocktheirrenewal,andkillcancercells14  Napabucasincouldhaveserioussideeffectsinhumans,asithasbeenshowntocausebonelossinmice.15 Itmayalsobepossibletocombinetwonon-lethaldrugtogetherinawaythatwillkillCSCs.Aninternationalcollaborationlookingintothisfoundthatcombininganantibiotic(doxycycline)withvitaminCwaseffectiveattargetingCSC-likebreastcancercells.16 LearnmoreaboutMDRanddrugresistance.Learnmoreaboutcancercelldeath(apoptosis).   CancerDevelopmentSummary Introduction Allofourcellshavesimilarstructuresandshareamajorityoftheirfunctions. Cancersmaybecategorizedintofivebasictypesbasedonthecelloforigin: Carcinoma-epithelialcells Sarcoma-muscle,bone,cartilage,fat,orconnectivetissue Leukemia-bloodcellsortheirprecursors Lymphoma-bonemarrowderivedcells;canceraffectsthelymphaticsystem Myeloma-specificbloodcells;Blymphocytes(B-cells) StagesofTumorProgression Tumorstypicallyprogressisastepwisefashion: Hyperplasia-cellsdividetoomuchbutappearnormal Dysplasia-thetumorcellsandtissueappearabnormal Carcinomainsitu-tumorcontainsprimarilyalteredcellsandisgrowinglarger;ithasnotleftthesiteoforigin MalignantCancer-tumorhasbeguntoinvadenearbyordistanttissues Benigntumorsremainintheirinitiallocationanddonotinvadeothertissues. InitiatorsandPromoters Initiationisthefirststepinthetwo-stagemodelofcancerdevelopment. Initiatorscauseirreversiblechanges(mutations)toDNAthatincreasecancerrisk. Promotionisthesecondstepinthetwo-stagemodelofcancerdevelopment. Onceacellhasbeenmutatedbyaninitiator,itissusceptibletotheeffectsofpromoters. Promotersincreasetheproliferationofcellsandtherearetwomaintypes: Specific-interactwithreceptorsonorinparticulartargetcells. Nonspecific-altergeneexpressionwithoutthepresenceofaknownreceptor Carcinogens Substancesthatcancausecancerareknownascarcinogens. Theprocessofcancerdevelopmentiscalledcarcinogenesis. Certaincarcinogenicchemicalsareassociatedwithanincreasedriskofspecificcancersduetochronicexposure. Oneofthemostpotentcarcinogensinhumansisbenzo[a]pyrene,acompoundfoundincigarettesmoke. VirusesandBacteria Certainvirusesandbacteriahavealsobeenassociatedwiththeinitiationandpromotionoftumorgrowth. Somevirusescausecancerdirectlybyaffectingcelldivisionwhileothervirusescausecancerbycausingchronicinflammationorreducingimmunesystemfunction. ChronicInflammation Chronicinflammationisanimportantfactorintumordevelopment. Inflammationcanleadtoalteredbehaviorofcells,stimulationofbloodvesselgrowth(angiogenesis)andtissueremodeling. Markersofinflammationcorrelatewithaworseprognosisforcancerpatients. 1Urry,L.A.,Cain,M.L.,Wasserman,S.A.,Minorsky,P.V.,&Reece,J.B.(2017).CampbellBiology(11thed.).Pearson. 2Weinberg,RA."FindingtheAnti-Oncogene."ScientificAmerican(1988).259(3):44-51.[PUBMED] 3YamagiwaK,IchikawaK.ExperimentalStudyofthePathogenesisofCarcinoma.JCancerRes3:1-29(1918).[http://caonline.amcancersoc.org/cgi/content/abstract/27/3/174] 4 a b c d TrollW,WiesnerR.Theroleofoxygenradicalsasapossiblemechanismoftumorpromotion.AnnuRevPharmacolToxicol.1985;25:509-28.[PUBMED] 5 a b c d e Pitot,H.C.,Goldsworthy,T.,Moran,S.Thenaturalhistoryofcarcinogenesis:Implicationsofexperimentalcarcinogenesisinthegenesisofhumancancer.JournalofSupramolecularStructureandCellularBiochemistry;Volume17,Issue2,Pages133146.PublishedOnline:19Feb2004. 6YamagiwaK,IchikawaK.ExperimentalStudyofthePathogenesisofCarcinoma.JCancerRes3:1-29(1918).[http://caonline.amcancersoc.org/cgi/content/abstract/27/3/174] 7Alberts,B.,Johnson,A.,Lewis,J.,Raff,M.,Roberts,K.,&Walter,P.MolecularBiologyoftheCell;FourthEdition.23.Cancer.GarlandScience;NY.2002. 8 a b c MackenzieIC."CancerStemCells"AnnalsofOncology.2008Jul;19Suppl5:v40-3.[PUBMED] 9 a b c d BomanBM,WichaMS."CancerStemCells:AStepTowardtheCure"JournalofClinicalOncology.2008Jun10;26(17):2795-9.[PUBMED] 10StadtfeldM,NagayaM,UtikalJ,WeirG,HochedlingerK."InducedPluripotentStemCellsGeneratedWithoutViralIntegration."Science.2008Sep25.[PUBMED] 11LeeCJ,DoschJ,SimeoneDM."PancreaticCancerStemCells."JournalofClinicalOncology(2008);26(17):2806-12[PUBMED] 12 a b PanCX,ZhuW,ChengL."Implicationsofcancerstemcellsinthetreatmentofcancer."FutureOncology.2006Dec;2(6):723-31.[PUBMED] 13Powers,Virginia."NapabucasinClinicallyActiveinBothPancreaticandColonCancer."OncLive(2017).[ONCLIVE] 14BHO'Neil,etal."LBA-003Phase1b/IIstudyofcancerstemnessinhibitornapabucasinincombinationwithFOLFIRI+/−bevacizumab(bev)inmetastaticcolorectalcancer(mCRC)patients(pts)."AnnalsofOncology(2017).[ANNONCOL] 15Huang,X.,Jin,A.,Wang,X.,Gao,X.,Xu,H.,Chung,M.,etal.(2021).NapabucasinInducesMouseBoneLossbyImpairingBoneFormationviaSTAT3.FrontiersInCellAndDevelopmentalBiology,9,648866.http://doi.org/10.3389/fcell.2021.648866(Originalworkpublished12/2021AD)[PUBMED] 16DeFrancesco,E.(2017).VitaminCandDoxycycline:Asyntheticlethalcombinationtherapytargetingmetabolicflexibilityincancerstemcells(CSCs).Oncotarget,8(40),67269-67286.http://doi.org/10.18632/oncotarget.18428(Originalworkpublished09/2017AD)[PUBMED] Top