肿瘤分子生物学[1]肿瘤的本质.ppt

Page1,肿瘤细胞生物学,目的：为生命科学领域研究生开设的，以提供肿瘤生物学的基本知识（现代概念？）细胞生物学课程中主要介绍了正常细胞的结构、功能、组织、信号转导、实际上肿瘤细胞,免疫细胞,神经细胞,以及干细胞均应在细胞的范畴内。病理学关于肿瘤则主要是从组织形态,临床肿瘤学强调诊断和治疗。而对肿瘤的更深入的了解,从根本上解决诊断治疗,肿瘤细胞生物学的研究应是根本.基本内容：肿瘤研究是一个极其宽泛的领域，我们集中于临床之外，但与临床紧密相关的肿瘤发生、发展、浸润、转移，与宿主的相互作用、转归等行为的生物学机制。考核：.。,Page2,Page3,Ultimately，weconcluded,cancerimmunotherapypassesthetest.,Page4,Itdoessobecausethisyear,clinicaltrialshavecementeditspotentialinpatientsandswayedeventheskeptics.Thefieldhumswithstoriesoflivesextended:thewomanwithagrapefruit-sizetumorinherlungfrommelanoma,aliveandhealthy13yearslater;the6-yearoldneardeathfromleukemia,nowinthirdgradeandinremission;themanwithmetastatickidneycancerwhosediseasecontinuedfadingawayevenaftertreatmentstopped.Astheanecdotescoalesceintodata,theresanotherlayer,too,asenseofparadigmsshifting.Immunotherapymarksanentirelydifferentwayoftreatingcancerbytargetingtheimmunesystem,notthetumoritself.20DECEMBER2013VOL342:1432SCIENCE,Page5,CancerImmunotherapyTHEWARONCANCERBEGANALITTLEMORETHAN40YEARSAGOASANATIONALRESEARCHPROGRAMtoradicallyimprovethesurvivalofpatientswithcancer,aleadingcauseofdeathintheUSandworldwide.Themainweaponsdeployedhavebeensurgery,radiation,andchemotherapy,treatmentsthatoftencarryrisksand/orcauseadversesideeffects.Althoughsomeformsofcanceryieldtothesetherapy,notalldo,andthusmortalityremainshigh.Tothatlistwenowaddafourthweapon,cancerimmunotherapy.Constructedoverdecades,ithasbeguntodemonstratesuchpromisingresultsincancerpatientsthatwehaveselecteditastheBreakthroughoftheYearfor2013.,Page6,WaronCancerMoreSuccessfulThanPerceived,March11,2010Overall,theratesofcancer-relatedmortalityhavesubstantiallydeclinedintheUnitedStates.AccordingtotheresultsofanewstudypublishedonlineMarch9inPLoSONE,cancerdeathrateshavedeclinedinbothmenandwomen,whethertheyaremeasuredagainstbaselineratesin1970/71,whentheNationalCancerActwasinitiated,oragainstthepeakratesseen1990/91.,Page7,Mortalityrates(per100,000)increasedinmenfrom249.3in1970to279.8in1990,andthendeclinedto221.1in2006.Thisyieldedanetdeclineof21%from1990,apeakyear,andadropof11%since1970,abaselineyearInwomenrosefrom163.0in1970to175.3in1991,andthendecreasedto153.7in2006.Thiswasanetdeclineof12%and6%fromthe1990and1970rates,respectively.Thedeclineincancerdeathratessince1990hasresultedprimarilyfromreductionsintobaccouse,increasedscreeningthatallowsforearlydetectionofseveralcancers,andmodesttolargeimprovementsintreatmentforspecificcancers,Page8,FutureTrendsResearchatthemolecularlevelandunderstandingthemoleculardriversandtriggersofcancerisessentialtodevelopingbettertreatments.Wearerecognizingthattreatingalllungcancerinthesamemannerisathingofthepast.Thekeyisnowmoreindividualizedcare,whichisbasedonspecifictypesofbiology.,肿瘤的本质,XianJiaotongUniversity,2016.2.,Page10,Page11,Page12,bornFeb.25,1682,Forl,ItalydiedDec.5,1771,PaduaItaliananatomistandpathologistwhoseworkshelpedmakepathologicalanatomyanexactscience.,Page13,Page14,Page15,Page16,Hippocrates(460-375BC),thefatherofmedicine,wasthefirsttodividetumorsintotwolargegroupsaccordingtotheirbehavior,（1）theinnocuoustumors,whichincludedswellingsandlumpsofvariouskinds(probablybothnonneoplasiticandneoplastic)（2）thedangeroustumors,whichkilledthepatients(probablyrepresentingpredominantlymalignantneoplasms).,肿瘤的概念,Page17,Galen(AD131-201prominentGreekphysician,surgeonandphilosopherintheRomanempire）dividedtumorsintothreecategories:(1)tumoraccordingtonature,e.g.,pregnancy.(2)tumorsexceedingnaturee.g.,inflammatoryandreparativetumors,callusaroundabonefracture;and(3)tumorcontrarytonature,e.g.,trueneoplasms.,Galenwasawareofthephenomenonoftumormetastasis.Hewasalsothefirsttotheorizeastothepossiblecauseofcancer,ascribingittoexcessofblackbile.Itissaidthathewastheonewhocoinedthetermsarcoma(Gr.sarx,genitivesarkos,flesh)underwhichheincludedvarioustumorswithafleshygrossappearance.,Page18,肿瘤的概念,肿瘤是机体在各种致瘤因素的作用下,局部组织的细胞异常增生而形成的新生物,这种新生物常表现为肿块.肿瘤细胞是从正常细胞转变而来的,但当它变为肿瘤细胞后就具有异常的形态、代谢及功能，它生长旺盛，呈相对无止境生长，与整个机体不协调，并在不同程度上失去了发育成熟的能力，有些甚至具有接近幼稚的胚胎细胞的表现。一旦形成肿瘤，即便是致瘤因子不存在，肿瘤细胞的生长和代谢仍能继续保持下去；当把这种肿瘤细胞接种到体外培养基中培养时这种特征依然存在（病理学卫生部统编教材第一版1979）。,Page19,肿瘤概念,Cancerisageneticdisease,arisingfromanaccumulationofmutationsthatpromoteclonalselectionofcellswithincreasinglyaggressivebehavior.Thevastmajorityofmutationsincanceraresomaticandarefoundonlyinanindividualscancercells.However,about1%ofallcancersariseinindividualswithanunmistakablehereditarycancersyndrome.Theseindividualscarryaparticulargermlinemutationineverycelloftheirbody.ScienceVol.278.no.5340,pp.10431050,7November1997,肿瘤是机体在各种致瘤因素的作用下，局部组织的细胞在基因水平上失去对其生长的正常调控，导致克隆性异常增生而形成的新生物（病理学卫生部统编教材第五版2001）。,Page20,Cancerisadiseaseofthegenome,whichisinvariablyalteredatmultiplesitesincancercells.Thegoalofcancerresearchistodefinethesemoleculardefectsandturnthesediscoveriesintoeffectivetreatmentandpreventionregimens.CancerCell,Vol1,37-47,February2002,Page21,FundamentaltotheoriginofallneoplasmsarethelossofresponsivenesstonormalgrowthcontrolsRobinsbasicpathology7thedition.2003Fundamentaltotheoriginofallneoplasmsareheritable(genetic)changesthatallowexcessiveandunregulatedproliferationthatisindependentofphysiologicgrowth-regulatorystimuli.Neoplasmsthereforeenjoyacertaindegreeofautonomyandmoreorlesssteadilyincreaseinsizeregardlessoftheirlocalenvironmentandthenutritionalstatusofthehost.Theirautonomyisbynomeanscomplete,however.Someneoplasmsrequireendocrinesupport,andsuchdependenciessometimescanbeexploitedtothedisadvantageoftheneoplasm.Robinsbasicpathology8thedition.2007,Page22,Ingeneral,neoplasmsareirreversible,andtheirgrowthis,forthemostpart,autonomous.Severalobservationsareimportant:Neoplasmsarederivedfromcellsthatnormallymaintainaproliferativecapacity.Thus,matureneuronsandcardiacmyocytesdonotgiverisetotumors.Atumormayexpressvaryingdegreesofdifferentiation,fromrelativelymaturestructuresthatmimicnormaltissuestoacollectionofcellssoprimitivethatthecelloforigincannotbeidentified.Thestimuliresponsiblefortheuncontrolledproliferationmaynotbeidentifiable.Neoplasiaarisesfrommutationsingenesthatregulatecellgrowth,deathorDNArepair.RUBINSPATHOLOGY:ClinicopathologicFoundationsofMedicine6thEdition2012,Page23,Nocompletelysatisfactorydefinitionofneoplasiaexists，ithasbeensurprisinglydifficulttodevelopanaccuratedefinition.InthePremolecularera,definitionoftheeminentBritishoncologistWillisremainsoneofthemostwidelycitedanduseful:Aneoplasmisanabnormalmassoftissue,thegrowthofwhichexceedsandisuncoordinatedwiththatofthenormaltissuesandpersistsinthesameexcessivemanneraftercessationofthestimuliwhichevokedthechange(WillisB.A.:thespreadofthetumorsinthehumanbody,London,1952.Butterworth&Co.),Page24,Inthemodernera,aneoplasmcanbedefinedasadisorderofcellgrowththatistriggeredbyaseriesofacquiredmutationsaffectingasinglecellanditsclonalprogeny.Thecausativemutationsgivetheneoplasticcellsasurvivalandgrowthadvantage,resultinginexcessiveproliferationthatisindependentofphysiologicgrowthsignals(Robbins&CotranPathologicBasisofDisease9thEd.2015),Page25,肿瘤是一种细胞性病肿瘤是一种基因病(遗传病)肿瘤是一种组织病(肿瘤性复杂组织的组织性疾病),Page26,Tumorsandderivedxenograftedtumorcelllines,Stromalcomponentsofseveralcommonlyoccurringcarcinoma,High-gradeinvasiveductalcarcinomaofthebreast,Coloncancer,Lobularcarcinomainsituofthebreast,Adenocarcinomaofthestomach,Hodgkinslymphoma,Page27,RecruitmentofendothelialprecursorcellsbymammaryCAFs,Normalstromaanddesmoplasticstroma,Page28,Page29,Tumorsarisefromnormaltissues组织/细胞学证据相似性、异型性（组织病理学)TumorsarisefrommanyspecializedcelltypesthroughoutthebodyEpitheliatissues(threeprimitivecelllayers)：Carcinoma(80%cancerdeath)Non-Epitheliatissues(Sarcoma/Hematopoieticmalignancy/Neuroectodermalmalignancy/others)Sometypesoftumorsdonotfitintothemajorclassifications,Page30,NormalvsHyperplasticepithelium,Cancersseemtodevelopprogressively,Metaplasticconversionofepithelia(metaplasticBarrettsepithelium),Dysplasticepithelium,Ductalcarcinomainsitu,Invasiveductalcarcinoma,Page31,Thegeneticalterationsofcancercellsareheritable.Asaresult,cellsharboringthesealterationsaresubjecttoDarwinianselection,withcellsbearingmutationsthatprovidethemwithgrowthorsurvivaladvantagesoutcompetingtheirneighborsandthuscomingtodominatethepopulation.Becausetheselectiveadvantagesareconferredonasinglecellthatultimatelygivesrisetothetumor,alltumorsareclonal(i.e.,theprogenyofonecell).,肿瘤是单克隆生长,Monoclonalityvspolyclonalityoftumors,Page32,glucose-6-phosphatedehydrogenase,chromasomeabrration,Todeterminewhetherallthecellsinatumormassshareacommon,highlyuniquegeneticorbiochemicalmarker.,Page33,Cancercellsexhibitanalteredenergymetabolism,Theenergymetabolismofmostcancercellsdiffersmarkedlyfromthatofnormalcells,firstreportedin1924byOttoWarburg,Page34,Cancersoccurwithvastlydifferentfrequenciesindifferenthumanpopulations日本人胃癌发病是美国人的6-8倍，第二代则和周围人相类似（环境与生活方式）中国人乳腺癌是美国人的1/6，排除遗传因素，美国人85%的乳腺癌是可以预防的中国广东的鼻咽癌发病高，即便是移居国外亦是如此美国一宗教信仰者反对吸烟，酗酒，提倡素食，因肿瘤死亡者是一般人群的1/2因此，避免明显的环境致癌因素，生活习惯，可以降低50%的肿瘤发生，而肿瘤在人群死亡中所占的比例仅为10%左右。,Page35,aSeeC.Muir,J.Waterhouse,T.Macketal.,eds.,CancerIncidenceinFiveContinents,vol.5.Lyon:InternationalAgencyforResearchonCancer,1987.ExcerptedbyV.T.DeVita,S.HellmanandS.A.Rosenberg,Cancer:PrinciplesandPracticeofOncology.Philadelphia:Lippincott,1993.,Page36,bRelativerisk:age-adjustedincidenceordeathrateinhighestcountryorarea(H)dividedbyage-adjustedincidenceordeathrateinlowestcountryorarea(L).Thesenumbersrefertoage-adjustedrates,forexample,therelativeriskofa60-year-olddyingfromaspecifictypeoftumorinonecountrycomparedwitha60-year-oldinanothercountry.cSeeP.Pisani,D.M.Parkin,F.BrayandJ.Ferlay,Int.J.Cancer83:1829,1999.Thissurveydividedthehumanpopulationinto23geographicareasandsurveyedtherelativemortalityratesofvariouscancertypesineacharea.,Page37,Theriskofcancersoftenseemtobeincreasedbyassignableinfluencesincludinglifestyle英国内科医生JohnHill,1761年，吸鼻咽者易患鼻癌，14年后，英国外科医生PercivallPott发现扫烟囱者易患阴囊癌，chimneysweeperguild强制成员每日洗澡，肿瘤发生明显下降。16世纪中期，捷克银矿工人肺癌发生率1839年意大利医生报道修女乳腺癌发生率高于常人6倍1949-1950两组关于吸烟与肺癌的报告，长期大量吸烟者肺癌发生率是常人的20倍,Page38,aAdaptedfromAmericanCancerSociety.CancerFacts&Figures1990.Atlanta:AmericanCancerSociety,Inc.bAlargenumberofcancersarethoughttobeprovokedbyadiethighincalories(seeSidebar9.10)actingincombinationwithmanyoftheselifestylefactors.,Page39,Relativeriskoflungcancerasafunctionofthenumberofcigarettessmokedperday,Therelativeriskindicatestheriskofcontractinglungcancercomparedwiththatofanonsmoker,whichissetat1.FromR.DollandA.B.Hill,BMJ2:739748,1950.,Page40,AdaptedfromS.Wilson,L.Jones,cancerandtheenvironment:Gene-EnvironmentInteraction,WashingtonDC.NationalAcademyPress,2002,Page41,Examplesofetiologicmysteries:epidemiologiccorrelationsbetweenenvironmental/lifestylefactorsandcancerincidencethatlackaclearexplanationofcausalmechanism,Page42,Specificchemicalagentscaninducec