肿瘤的生物学特性ppt课件.ppt

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 lengthis15 20kb Fiftyto200bpofthetelomericDNAshortensateachroundofmitosis WhenaverageDNAreachesacriticallyshortlength about4 7kb 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 andbothwereareliableprognosticmarkerinstageI IIIBCpatients 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 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 RESULTS 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 OverexpressionofTiam1inhepatocellularcarcinomaspredictspoorprognosisofHCCpatientsYiDing1 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 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 TheKrasG12Dknockdowncellsexhibitedasignificantdecreaseinmotility P 0 0001 invasion P 0 0001 anchorage dependent P 0 0001 andanchorage independentgrowth P 0 0001 proliferation P 0 005 andanincreaseincelldoublingtime P 0 005 invitroandadecreaseintheincidenceofmetastasesuponorthotopicimplantationintonudemice TheknockdownoftheKrasG12DalleleledtoasignificantincreaseintheexpressionofE cadherin mRNAandprotein bothinvitroandinvivo Thiswasassociatedwithadecreaseintheexpressionofphoshpo ERK 1 2 NF BandMMP 9 andtranscriptionfactorssuchas EF1 SnailandETV4 Furthermore theexpressionofseveralproteinsinvolvedincellsurvival invasionandmetastasiswasdecreasedintheKrasG12Dknockdowncells Conclusions TheresultsofthisstudysuggestthattheKrasG12DallelepromotesmetastasisinPCcellspartlythroughthedownregulationofE cadherin 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 BritishJournalofCancer104 1038 1048 15March2011 TheEnd