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首页 癌细胞生物学

癌细胞生物学.PDF

癌细胞生物学

槛外人
2010-10-23 0人阅读 举报 0 0 暂无简介

简介:本文档为《癌细胞生物学pdf》,可适用于自然科学领域

a:CancerBiology癌細胞生物學Cloneandclonalevolution增生中的細胞蜇伏的細胞ProliferativepotentialGivesrisetodifferentiatedcellsSelfrenewingPropertiesofstemcells(幹細胞)ProliferationDifferentiationDeathTransitProliferatingExitingRenewingCellularequilibrium(細胞平衡)ProliferationDifferentiationDeathCancer:disruptionofcellularequilibriumPostmitoticStemcellDifferentiatedNormalsenescentdifferentiatedcellBenigntumorGrademalignancyGradeormalignancySellandPierce,LabInvest:,StemcellsasthetargetofcarcinogensAnatomyofacancer:theprogressionofuterinecervixcarcinomaThedysplasicstateappearswhenneoplasticcellsbegintoreplacetheexistingepithelium,yettheystilldivideratherslowlyanddonotshowsignsofmalignancyThecarcinomainsitu,however,ismoredangerousneoplasticcellshavecompletelyreplacedtheepitheliumFinally,thecellsaccumulateadditionalmutationsthatallowthemtobreakthroughthebasallaminaandinvadeothertissuesWhilethedysplasicstateoftenspontaneouslyregresses,themalignantstatedoesnotWherearestemcellsNoteinpartF,thebravecellbustingthroughthebasallaminaThisisverybadfortheindividualwhohasthishappening,obviously……whichiswhythePapsmearissoimportantArepresentsnormalcells,Brepresentsdysplasticcellsthatareinavarietyofdifferentiatedstages,andCrepresentsinvasivecarcinomanotetheembryonicfeaturesofthecells(lownucleuscytoplasmratioisprettyclassic)Papsmears,unfortunately,areonlyasgoodasthepeopledoingandinterpretingthem,buttheyrepresentagoodfirsttesttodetectneoplasybeforeitgetsworseWhatisrequiredforMetastasis(轉移)Mustbeabletocrossthebasallamina(expresstypeIVcollagenase)Mustnotadheretoneighborcells„Inclassiccellculture,cellsformamonolayer„NeoplasticcellscontinuetogrowMustbeabletomigratethroughinterstitialfluidandbloodstreamtonewsitesThisis,ofcourse,thenormalsituation,inwhichcellsofepitheliamaintaincontactswiththebasallamina……butmetastaticcellsoftenexpresscollagenase,allowingthemtobreakdownthelaminaInaddition,theystopexpressinglamininreceptorsandhavecytoskeletalalterations……thatleadtotheabilitytomovepastthebasallaminaintounderlyingtissuesandeventuallythecirculatorysytemEventhoughatumorisclonal,allthecellsarenotaliketheydifferintheirabilitytoformmetastases,asthisexperimentclearlydemonstratesThecellsarepickingupadditionalmutationsastheydivide,accountingforthephenotypicdifferencesb:MolecularBiologyofCancer癌分子生物學OncogenesTumorsuppressorgenesNotethatcancerresultsONLYifthecellisexposedtoatumorpromoterrepeatedlyAFTERaninitiatorNotealsothatmultipleinitiatorsmayresultincancer(bottomtimeline)CanceronsetcorrelatesstronglywithageSporadic(noninherited)cancersarerarebeforeyearsofage,buttheriskclimbsdramaticallyafterthatOnaloglogplotliketheoneinpartB,therelationshiplookslinear,butitisactuallyrisingroughlyasthefifthpowernaphthylaminecausesbladdercancer,butonlydoessoafterseveralyearsThepointisthatexposuretoacarcinogenandthedevelopmentofcancercanbeyearsapart,pointingouthowdifficultitistoattachcausationtocancersShownhereisaneoplasticmassamongnormalcellsThetrickusedhereistoexaminewhichXhasbeeninactivatedinthecellsbyusingamarkerofsomesortThecellsaroundthemassexhibitrandominactivationofoneortheotherX,whilethecellsinthemassareallidenticalOthermarkerscanbeusedtodefinitivelydemonstratethattumorsareclonalentitiesCancersareclonaltheyarisefromasinglecellthatbecomesmalignant癌化過程中什麼基因改變了?Figure|ExampleofaproteinsignallingpathwayNatureReviewsDrugDiscovery()Clinicalproteomics:translatingbenchsidepromiseintobedsiderealityNeoplasticproteinsOncogenes(致癌基因)Growthfactorsandrelatedhormonesservingasligandsfortheirreceptors(EGF,TGFβ,PDGF,etc)Growthfactorreceptors(TKreceptors,Glinkedreceptors,Smadreceptors,etc)Intracellulartransducers(Gproteins,SHSHproteins,etc)IntracellularreceptorstranscriptionfactorsthatrealizetheultimateresultofthesignalCellcyclecontrolproteinsNeweradditionstothemenagerieTumorsuppressorgenes(抑癌基因):geneswhoseproductspreventtumorformationwhenmutant,tumorsresultApoptoticgenes(萎凋死亡基因):geneswhoseproductsnormallyinduceapoptosisindamagedcellsCheckpointproteinsthatassessDNAdamageinthecellCancer:GeneralEtiologyandPathogenesisCancer:GeneralEtiologyandPathogenesisCancerMolecularPathwaysCancerMolecularPathwaysDownstreameffectsinpresenceofligandNormalDownstreameffectsinabsenceofligandAbnormalNormally,aligandbindsandcausestheTKreceptortodimerize,elicitingthedownstreameffectsButsupposetheNterminalregionisdeleted,allowingreceptordimerizationwhetherthesignalisthereornotthencellscouldrespondinappropriatelytoaLACKofsignalasifitwasthere!Otherexamplesincludealigandthatbindsbutdoesnotletgo,producingacontinuousresponse…orbindingofreceptorstothewrongsubstrateGeneticMechanismsofTumorsGeneticMechanismsofTumors•Genedeletionsamplifications•Mutations•Insertional•PointMutations•GeneticInstability•MicrosatelliteInstability(MSI)•ChromosomalInstability(CIN)GeneticInstabilityinTumorsGeneticInstabilityinTumors•ChromosomalInstability•Telomereshortening•Mismatchrepair(MMR)genes•MicrosatelliteInstabilityCauseandortumorprogressionbyproductProgressiveAcquisitionofNeoplasticFeatures:ProgressiveAcquisitionofNeoplasticFeatures:AprocessofclonalevolutionAprocessofclonalevolutionHallmarksofCancerCellsHallmarksofCancerCells•Selfmaintainedreplication•Longersurvival•Geneticinstability•Capableofinducingneoangiogenesis•Capableofinvasionandmetastasis–Lackofresponsetoinhibitoryfactors–SelfsustainedproliferationHallmarksofCancerCellsHallmarksofCancerCells•Selfmaintainedreplication•Longersurvival•Geneticinstability•Capableofinducingneoangiogenesis•Capableofinvasionandmetastasis–Apoptosisdownregulation–TelomerasereactivationHallmarksofCancerCellsHallmarksofCancerCells•Selfmaintainedreplication•Longersurvival•Geneticinstability•Capableofinducingneoangiogenesis•Capableofinvasionandmetastasis–Mutagenicagents–Cooperativegeneticdamage–DefectiverepairsystemsHallmarksofCancerCellsHallmarksofCancerCells•Selfmaintainedreplication•Longersurvival•Geneticinstability•Capableofinducingneoangiogenesis•CapableofinvasionandmetastasisBasicBiologicFeaturesofBasicBiologicFeaturesofNeoplasmsNeoplasmsOncogenicLesion(egRAS,MYC,EFActivation)OncogenicOncogenicLesionLesion(egRAS,MYC,EFActivation)(egRAS,MYC,EFActivation)DifferentiationAbnormalProliferationAngiogenesisInvasionSenescenceApoptosisMultistepMultistepTumorigenesisTumorigenesisSporadicvsfamilialcancersSomecancersseemtooccursporadicallythatis,withnoobviousinheritancepatternThesecancersaretypicallyduetomutationeventsaccumulatingoverthelifeoftheindividual(explainingwhycanceristypicallyadiseaseofolderanimals)OthercancersstrikeearlyandsomemayseemtobeMendeliantraitstheseareinheritedpredispositionsWhat’sthedifferenceTheansweristhatearlyonsetandinheritedcancersaresituationswhereonecopyofanoncogeneisalreadymutantonlyadditionalhitisrequiredAsshownhere,therearemanywaysinwhichanormalcopyofanoncogenecouldbemutated,andallofthesehavebeenobservedBasicMechanisms:BasicMechanisms:GeneralPathogenesisGeneralPathogenesisColonCancerasaParadigmColonCancerasaParadigmColon:AnatomyandFunctionFUNCTION•Storage•WaterabsorptionANATOMYHISTOLOGYCommonFamilialColonCancerHNPCCFAPFJPPJSSporadicColonCancerColonCancer:HeredityvsEnvironmentSporadicCancer~FJPPJS<FAP<HNPCCCFCCAdaptedfromBurt,Gastro,ColonAdenomas:PathologyColonAdenocarcinomaAdenomaCarcinomaSequenceAPCqLOHKRASp,q,qTPpq,q,pPRL>yearsyears~yearAsstatedbefore,numerouschangesmustoccurformetastaticcancertodevelopIncoloncancer,itcanalmostbepredictedwhatthecourseofgenealterationwillbe,asisshownbythis“timeline”ofeventsNoticetheAPClossatthestartandthelossofptoproduceacarcinomainsituSoeventhoughsomeonewithinheritedAPClosshasbenignpolyps,itdoesn’tnecessarilymeantheywillbecomecarcinomas…butthechanceismuchhigherCancerAdiseaseofgene(DNA)CarcinogenesisisacontinuousevolutionalprocessChangesinDNAgenomeRNAProteinTumormarkers(DNA,RNA,Protein)EarlydetectionispossibleTargetingtherapyisafeasiblegoala:CancerBiology�癌細胞生物學WhatisrequiredforMetastasis(轉移)b:MolecularBiologyofCancer�癌分子生物學癌化過程中什麼基因改變了?NeoplasticproteinsOncogenes(致癌基因)NeweradditionstothemenagerieCancer:GeneralEtiologyandPathogenesisCancerMolecularPathwaysGeneticMechanismsofTumorsGeneticInstabilityinTumorsProgressiveAcquisitionofNeoplasticFeatures:�AprocessofclonalevolutionHallmarksofCancerCellsHallmarksofCancerCellsHallmarksofCancerCellsHallmarksofCancerCellsBasicBiologicFeaturesofNeoplasmsSporadicvsfamilialcancersCancer

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