肿瘤的生物学特性课件

肿瘤的生物化学特性1可编辑课件PPT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2可编辑课件PPT3可编辑课件PPT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4可编辑课件PPTDNA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5可编辑课件PPT(A)ClassificationofhumanDNAtopoisomerases.TypeIBaretheonlyenzymesthatformcleavagecomplexes(cc)with30-phosphotyrosyl(30-P-Y)intermediates.(C)NoncovalentbindingoftypeIBenzymes.(D)Schemeofthe30phosphotyrosinecovalentbondintheTop1cc.Thearrowindicatesthereversible(religation)reaction,whichisfavoredundernormalconditions.G)Schemeofthe50-phosphotyrosinecovalentbondintheTop2cc.6可编辑课件PPT7可编辑课件PPTItisthoughtthatlengthorintegrityofchromosomeendisusedasamitoticcountingmechanisminvitro核酸代谢物质代谢及酶的变化端粒酶EachmammalianchromosomeendhasadistinctiveDNA-proteinstructure,whichpreventsthedegradationandfusionofchromosomeendsbyhelpingdistinguishchromosomeendsfromadoublestrandbreakinthegenomicDNA.8可编辑课件PPTMammalianhaveastretchofasimplerepeatsequenceunit(TTAGGG)andin,lengthis15–20kb.Fiftyto200bpofthetelomericDNAshortensateachroundofmitosis.WhenaverageDNAreachesacriticallyshortlength,about4–7kb,isarrestedIrreversibly.核酸代谢端粒酶物质代谢及酶的变化9可编辑课件PPT物质代谢及酶的变化核酸代谢蛋白质代谢糖代谢酶系统10可编辑课件PPT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11可编辑课件PPT肿瘤细胞的分化各种不同类型细胞(分化细胞)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12可编辑课件PPT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。13可编辑课件PPT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14可编辑课件PPT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15可编辑课件PPT肿瘤细胞的生长免疫组织化学方法Severalmonoclonalantibodiesreactingwithdifferentproliferatingcellnuclearantigenshavebeendescribed,suchasPCNA,Ki-67andMIB1,KiS1andothers.TheKi-67/MIB1proteinhasaprognosticvalueformanytypesofmalignanttumors.Ki-67OnlypaperspublishedinEnglishinpeerreviewedjournalsbeforeJune2004thatincludeatleast100evaluablepatientswereselected.Inaddition,theprognosticandpredictiveroleoftheproliferativemarkershadtobeassessedthroughmultivariateanalyses.Onehundredandthirty-twopapersfulfilledthesecriteriaand159516patientsanalyzed.16可编辑课件PPT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.CyclinEisthelimitingfactorforG1phaseprogressionandSphaseentryRecently,severalsplicevariantsofcyclinE1,whicharenotpresentinnormalcells,havealsobeendiscovered;whichstimulatecellstoprogressthroughthecellcyclemuchmoreefficientlythanthefulllengthcyclinE117可编辑课件PPTCyclinEwasprognosticinsevenoutof10studies.肿瘤细胞的生长免疫组织化学方法细胞周期蛋白TheoverexpressionofcyclinEwasaccompaniedbytheappearanceoflowmolecularweight(LMW)isoforms,andbothwereareliableprognosticmarkerinstageI–IIIBCpatients.HighlevelsofcyclinE1werepredictiveofresistancetotamoxifenadjuvanttherapyin108node-positiveBCpatients,independentlyofERstatus.18可编辑课件PPTCyclinD1肿瘤细胞的生长细胞周期蛋白D-typecyclinsareotherkeyregulatorproteinsoftheG1phaseprogression.Theproteinissynthesizedinresponsetogrowthfactors;itslevelsreachamaximuminthemid-G1phaseofthecellcycleandthenbegintodrop.ItappearsthattheassociationofcyclinD1toCdkiscrucialtodrivecellstotherestrictionpointwherethecelliscommittedtodivide19可编辑课件PPTAstrongcorrelationbetweenoverexpressionofcyclinD1andHR-positivityhasbeenreportedinthemajorityoftrials,butcyclinD1doesnotappeartobeastrongprognosticmarker.Infact,itsoverexpressionhasbeenassociatedwithbetterRFSinonlyonestudyCyclinD1肿瘤细胞的生长细胞周期蛋白20可编辑课件PPT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。21可编辑课件PPT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.22可编辑课件PPTFigure1.DevelopmentoflymphaticvesselsinembryogenesisandcancerSomeoftheproteinsthatareimportantintheseeventsareshownunderneatheachsection.Arrowsdenotethedirectionoflymphflowinthelymphaticvessels.23可编辑课件PPT转移metastasis肿瘤的生长与扩散肿瘤的扩散方式血道转移24可编辑课件PPT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。25可编辑课件PPT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26可编辑课件PPT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27可编辑课件PPT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；P28可编辑课件PPT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29可编辑课件PPT肿瘤细胞扩散的过程机制细胞黏附与细胞黏附分子SelectinfamilycancercellsadheretobyaprocesssimilartothatofLChoming.Inthismodel,cellsinflowarecapturedontheendothelialsurface.30可编辑课件PPTtransientadhesiveinteractionsbycellswithendothelialselectins(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Selectinfamily31可编辑课件PPT肿瘤细胞扩散的过程机制细胞黏附与细胞黏附分子CD44Atransmembraneprotein

EssentialforthehomingandpropertiesofleukemicCells,

CD44hasalsobeenfoundtosupportanchorage-independentgrowthinvitroandtumorgrowthandinexperimentalmodelsofsolidcancers

32可编辑课件PPT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33可编辑课件PPT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34可编辑课件PPT肿瘤血管生成肿瘤细胞向周围组织的浸润35可编辑课件PPT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36可编辑课件PPTFig.1Switchingontheangiogenicphenotypeintumorsbygeneticandepigeneticfactors.Bothmalignantandnonmalignantcellsproducemultipleangiogenicfactorsandcytokinestoinducetumorneovascularization.Endogenousangiogenesisinhibitorsaredownregulatedtosupporttheangiogenicphenotype37可编辑课件PPT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.

38可编辑课件PPT转移灶的形成和生长39可编辑课件PPT肿瘤侵袭和转移相关基因Nm23基因NM23-H1andNM23-H2inhumanNucleosidediphosphatekinases(NDPKs)catalyzetheexchangeofγ-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40可编辑课件PPT肿瘤侵袭和转移相关基因肿瘤转移相关基因mtal41可编辑课件PPT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-celllymphomainvasionandmetastasis1[Homosapiens]ZhonghuaBingLiXueZaZhi.2009Apr;38(4):268-72.[OverexpressionofTiam1geneanditsrelationshipwithinvasiveandmetastaticabilityofnasopharyngealcarcinoma].[ArticleinChinese]ZhangXM,DingY,ChenJZ,JinH,YuLN,LiYF,DingYQ.Currently,manyGEFs,includingVav1,LARG,BcrandT-lymphomainvasionandmetastasis1(Tiam1),havebeenidentifiedasoncogenes.42可编辑课件PPTRESULTS:Tiam1overexpressionsignificantlyincreasedtheabilitiesofadhesion,migratoryandinvasionofC666-1andCNE1cells,comparingwiththatofthecontroluntransfectedcells(P<0.05).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。。43可编辑课件PPTOverexpressionofTiam1inhepatocellularcarcinomaspredictspoorprognosisofHCCpatientsYiDing1,BinChen2,ShuangWang3,LiangZhao3,JuanzhiChen3,YanqingDing3,LonghuaChen1*andRongchengLuo2*Int.J.Cancer:124,653–658(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。。44可编辑课件PPT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-cadherinBritishJournalofCancer104,1038-1048(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，45可编辑课件PPTResults:TheKrasG12Dknockdowncellsexhibitedasignificantdecreaseinmotility(P<0.0001),invasion(P<0.0001),anchorage-dependent(P<0.0001)andanch