肿瘤的生物学特性ppt课件VIP

.,肿瘤的生物化学特性,.,物质代谢及酶的变化,肿瘤细胞的分化,肿瘤细胞的生长,肿瘤细胞扩散的过程机制,肿瘤侵袭和转移相关基因,.,.,核酸代谢,核酸增多是肿瘤迅速生长的物质基础,DNA拓扑异构酶,物质代谢及酶的变化,端粒酶,.,DNA拓扑异构酶,存在于细胞核内的一类酶，他们能够催化DNA链的断裂和结合，从而控制DNA的拓扑状态。,DNA拓扑异构酶通过形成短暂的单链裂解-结合循环，催化DNA复制的拓扑异构状态的变化,核酸代谢,物质代谢及酶的变化,.,(A)ClassificationofhumanDNAtopoisomerases.TypeIBaretheonlyenzymesthatformcleavagecomplexes(cc)with30-phosphotyrosyl(30-P-Y)intermediates.,(C)NoncovalentbindingoftypeIBenzymes.(D)Schemeofthe30phosphotyrosinecovalentbondintheTop1cc.Thearrowindicatesthereversible(religation)reaction,whichisfavoredundernormalconditions.G)Schemeofthe50-phosphotyrosinecovalentbondintheTop2cc.,.,.,Itisthoughtthatlengthorintegrityofchromosomeendisusedasamitoticcountingmechanisminvitro,核酸代谢,物质代谢及酶的变化,端粒酶,EachmammalianchromosomeendhasadistinctiveDNA-proteinstructure,whichpreventsthedegradationandfusionofchromosomeendsbyhelpingdistinguishchromosomeendsfromadoublestrandbreakinthegenomicDNA.,.,Mammalianhaveastretchofasimplerepeatsequenceunit(TTAGGG)andin,lengthis1520kb.Fiftyto200bpofthetelomericDNAshortensateachroundofmitosis.WhenaverageDNAreachesacriticallyshortlength,about47kb,isarrestedIrreversibly.,核酸代谢,端粒酶,物质代谢及酶的变化,.,物质代谢及酶的变化,核酸代谢,蛋白质代谢,糖代谢,酶系统,.,物质代谢及酶的变化,酶系统,增殖相关和分化相关的酶,转化相关和演进相关的酶,细胞恶变的指标。,主要正常细胞发生转化，总可出现这类酶活性的改变。,演进相关的酶,酶活性于恶性程度呈平行关系的酶,转化相关,.,肿瘤细胞的分化,同一来源的幼稚细胞,?,分化的概念,特定的生理功能特定的生化特征特定的形态结构,.,稳定性全能性选择性条件可逆性,细胞分化特点:,未分化恶性肿瘤是由于起源组织中的干细胞丧失了分化的能力。,.,肿瘤细胞分化异常的机制,遗传学改变,信号转化异常,微环境的影响,诱导分化治疗肿瘤,.,肿瘤细胞的生长,细胞增殖活性的原位检测方法及意义,细胞增殖活性：,细胞增生快慢的能力,DNA含量测定,确定增生细胞的比例,DNAploidyandproliferativeactivityasrepresentedbytheS-phasefraction(SPF).,AlinkexistsbetweenhighSPFvaluesandincreasedriskofrecurrenceanddeathforpatientswithprimaryBC,Flowcytometry法,.,肿瘤细胞的生长,免疫组织化学方法,Severalmonoclonalantibodiesreactingwithdifferentproliferatingcellnuclearantigenshavebeendescribed,suchasPCNA,Ki-67andMIB1,KiS1andothers.,TheKi-67/MIB1proteinhasaprognosticvalueformanytypesofmalignanttumors.,Ki-67,OnlypaperspublishedinEnglishinpeerreviewedjournalsbeforeJune2004thatincludeatleast100evaluablepatientswereselected.Inaddition,theprognosticandpredictiveroleoftheproliferativemarkershadtobeassessedthroughmultivariateanalyses.Onehundredandthirty-twopapersfulfilledthesecriteriaand159516patientsanalyzed.,.,肿瘤细胞的生长,免疫组织化学方法,细胞周期蛋白,Thedifferentcyclins：theconcentrationriseandfallatspecificstagesthroughoutthecellcycle,haveatemporallydistinctandhighlyregulatedpatternofexpression,i.e.theyaresynthesizedanddegradedatspecificstagesofthecellcycle.,CyclinEisthelimitingfactorforG1phaseprogressionandSphaseentry,Recently,severalsplicevariantsofcyclinE1,whicharenotpresentinnormalcells,havealsobeendiscovered;whichstimulatecellstoprogressthroughthecellcyclemuchmoreefficientlythanthefulllengthcyclinE1,.,CyclinEwasprognosticinsevenoutof10studies.,肿瘤细胞的生长,免疫组织化学方法,细胞周期蛋白,TheoverexpressionofcyclinEwasaccompaniedbytheappearanceoflowmolecularweight(LMW)isoforms,andbothwereareliableprognosticmarkerinstageIIIIBCpatients.,HighlevelsofcyclinE1werepredictiveofresistancetotamoxifenadjuvanttherapyin108node-positiveBCpatients,independentlyofERstatus.,.,CyclinD1,肿瘤细胞的生长,细胞周期蛋白,D-typecyclinsareotherkeyregulatorproteinsoftheG1phaseprogression.,Theproteinissynthesizedinresponsetogrowthfactors;itslevelsreachamaximuminthemid-G1phaseofthecellcycleandthenbegintodrop.ItappearsthattheassociationofcyclinD1toCdkiscrucialtodrivecellstotherestrictionpointwherethecelliscommittedtodivide,.,AstrongcorrelationbetweenoverexpressionofcyclinD1andHR-positivityhasbeenreportedinthemajorityoftrials,butcyclinD1doesnotappeartobeastrongprognosticmarker.Infact,itsoverexpressionhasbeenassociatedwithbetterRFSinonlyonestudy,CyclinD1,肿瘤细胞的生长,细胞周期蛋白,.,肿瘤的生长与扩散,肿瘤的扩散方式,直接蔓延,转移,metastasis,瘤细胞从原发部位侵入淋巴管、血管和体腔，,扩散到其它部位，形成与原发瘤相同的肿瘤。,.,转移,metastasis,肿瘤的生长与扩散,肿瘤的扩散方式,淋巴道转移,Lymphaticmetastasisisapredictorofpooroutcomeinmanysolidmalignancies.,Thepresenceoflymphnodemetastasesdecreasesthe5-yearsurvivalofmelanomapatientsindependentofotherprognosticfactorsoftheprimarytumor.,.,Figure1.DevelopmentoflymphaticvesselsinembryogenesisandcancerSomeoftheproteinsthatareimportantintheseeventsareshownunderneatheachsection.Arrowsdenotethedirectionoflymphflowinthelymphaticvessels.,.,转移,metastasis,肿瘤的生长与扩散,肿瘤的扩散方式,血道转移,.,转移,metastasis,肿瘤的生长与扩散,肿瘤的扩散方式,种植性转移,体腔内脏器的肿瘤蔓延至器官表面时，瘤细胞可脱落种植于体腔和各器官表面形成多数转移瘤。,.,肿瘤细胞扩散的过程机制,肿瘤侵袭是转移的前提；,侵袭和转移的步骤：,脱离原发瘤群体,向周围组织浸润,与局部血管或淋巴管密切接触，穿过其管壁,穿透管壁，在基质中增生,转移灶的形成和生长,.,肿瘤细胞扩散的过程机制,细胞黏附与细胞黏附分子,侵袭和转移的步骤：,脱离原发瘤群体,以配体核受体结合的形式，使细胞间发生粘连,integrin,跨膜糖蛋白,十六种a亚单位和8种b亚单位,.,肿瘤细胞扩散的过程机制,细胞黏附与细胞黏附分子,cadherin,与细胞骨架连接,人类至少有10多种钙粘蛋白,E；N；P,.,肿瘤细胞扩散的过程机制,细胞黏附与细胞黏附分子,IgSF,跨膜蛋白,具有与Ig类似的结构,.,肿瘤细胞扩散的过程机制,细胞黏附与细胞黏附分子,Selectinfamily,cancercellsadheretobyaprocesssimilartothatofLChoming.Inthismodel,cellsinflowarecapturedontheendothelialsurface.,.,transientadhesiveinteractionsbycellswithendothelialselectins(rolling),andfirmlyanchoredon(firmadhesion)toenableentryintotheunderlyingtissue.Theselectins,particularlyE-selectin,arerecognizedtomediateadhesionandthuspotentiateofcertaincancers,肿瘤细胞扩散的过程机制,细胞黏附与细胞黏附分子,Selectinfamily,.,肿瘤细胞扩散的过程机制,细胞黏附与细胞黏附分子,CD44,Atransmembraneprotein,EssentialforthehomingandpropertiesofleukemicCells,CD44hasalsobeenfoundtosupportanchorage-independentgrowthinvitroandtumorgrowthandinexperimentalmodelsofsolidcancers,.,肿瘤细胞扩散的过程机制,肿瘤细胞从原发灶分离的机制,肿瘤细胞表面黏附分子减少。,癌细胞钙含量降低,恶性肿瘤细胞间连接结构数量减少,肿瘤细胞表面电荷增加,.,肿瘤细胞向周围组织的浸润,细胞外基质的降解,瘤细胞的运动,趋化因子的作用,肿瘤血管生成,.,肿瘤血管生成,肿瘤细胞向周围组织的浸润,.,肿瘤血管生成,肿瘤组织中微血管的来源,瘤细胞生成的多种生长因子,诱导瘤体生成微血管,残存于流体的宿主血管逐渐变为肿瘤血管,VEGF是迄今鉴定出来的最重要的血管生成因子,.,Fig.1Switchingontheangiogenicphenotypeintumorsbygeneticandepigeneticfactors.Bothmalignantandnonmalignantcellsproducemultipleangiogenicfactorsandcytokinestoinducetumorneovascularization.Endogenousangiogenesisinhibitorsaredownregulatedtosupporttheangiogenicphenotype,.,肿瘤细胞侵入血管和淋巴管,侵入血管和淋巴管,在循环中运行到达远处部位,Fig.1.SchematicdiagramshowinghowproductionofVEGF-CandVEGF-Cintumorscaninducelymphangiogenesis,leadingtoincreasedlymphaticvesseldensityinthevicinityofthetumor,andsubsequentlytometastasisofinvasivetumorcellsviathelymphvessels.,Fig.1.,.,转移灶的形成和生长,.,肿瘤侵袭和转移相关基因,Nm23基因,NM23-H1andNM23-H2inhuman,Nucleosidediphosphatekinases(NDPKs)catalyzetheexchangeof-phosphatebetweennucleoside(and2-deoxynucleoside)triphosphatesanddiphosphateswithformationofahigh-energyphosphohistidineintermediate(ParksandAgarwal1973).TheyareencodedbytheNMEgenes(alsoknownasNM23).,参与调节细胞内微管系统的状态,高度表达nm23表现为低转移属性,.,肿瘤侵袭和转移相关基因,肿瘤转移相关基因,mtal,.,肿瘤侵袭和转移相关基因,Tiam1基因,鼠T淋巴细胞瘤中克隆出来的基因。,产物具有1591个氨基酸残基，,把蛋白质锚定在质膜上,TIAM1T-celllymphomainvasionandmetastasis1Homosapiens,ZhonghuaBingLiXueZaZhi.2009Apr;38(4):268-72.OverexpressionofTiam1geneanditsrelationshipwithinvasiveandmetastaticabilityofnasopharyngealcarcinoma.ArticleinChineseZhangXM,DingY,ChenJZ,JinH,YuLN,LiYF,DingYQ.,Currently,manyGEFs,includingVav1,LARG,BcrandT-lymphomainvasionandmetastasis1(Tiam1),havebeenidentifiedasoncogenes.,.,RESULTS:Tiam1overexpressionsignificantlyincreasedtheabilitiesofadhesion,migratoryandinvasionofC666-1andCNE1cells,comparingwiththatofthecontroluntransfectedcells(P0.05).CONCLUSION:Tiam1expressioncorrelateswiththeinvasionandmetastasisofnasopharyngealcarcinomacells.,肿瘤侵袭和转移相关基因,Tiam1基因,鼠T淋巴细胞瘤中克隆出来的基因。,.,OverexpressionofTiam1inhepatocellularcarcinomaspredictspoorprognosisofHCCpatientsYiDing1,BinChen2,ShuangWang3,LiangZhao3,JuanzhiChen3,YanqingDing3,LonghuaChen1*andRongchengLuo2*,Int.J.Cancer:124,653658(2009)2008Wiley-Liss,Inc.,肿瘤侵袭和转移相关基因,Tiam1基因,鼠T淋巴细胞瘤中克隆出来的基因。,.,生长因子通过Ras信号通路，导致细胞增殖。,转染给NIH3T3细胞，引起大量侵袭和转移。,ActivatedKrasG12DisassociatedwithinvasionandmetastasisofpancreaticcancercellsthroughinhibitionofE-cadherin,BritishJournalofCancer104,1038-1048(15March2011),SRachagani,SSenapati,SChakraborty,MPPonnusamy,SKumar,LMSmith,MJainandSKBatra,肿瘤侵袭和转移相关基因,Ras基因,包括H-ras，K-ras和N-ras三类，,.,Results:TheKrasG12Dknockdowncellsexhibitedasignificantde