肿瘤的生物学特性课件

肿瘤的生物化学特性.u物物质代代谢及及酶的的变化化u肿瘤瘤细胞的分化胞的分化u肿瘤瘤细胞的生胞的生长u肿瘤瘤细胞胞扩散的散的过程机制程机制u肿瘤侵瘤侵袭和和转移相关基因移相关基因.核酸代核酸代谢核酸增多是核酸增多是肿瘤迅速生瘤迅速生长的物的物质基基础DNADNA拓扑异构拓扑异构酶u物物质代代谢及及酶的的变化化端粒端粒酶.DNADNA拓扑异构拓扑异构酶存在于存在于细胞核内的一胞核内的一类酶，他，他们能能够催化催化DNADNA链的的断裂和断裂和结合，从而控制合，从而控制DNADNA的拓扑状的拓扑状态。DNADNA拓扑异构拓扑异构酶通通过形成短形成短暂的的单链裂解裂解-结合循合循环，催化催化DNADNA复制复制的拓扑异构状的拓扑异构状态的的变化化 核酸代核酸代谢u物物质代代谢及及酶的的变化化.(A)Classification of human DNA topoisomerases.Type IB are the only enzymes that form cleavage complexes(cc)with 30-phosphotyrosyl(30-P-Y)intermediates.(C)Noncovalent binding of type IB enzymes.(D)Scheme of the 30 phosphotyrosine covalent bond in the Top1cc.The arrow indicates the reversible(religation)reaction,which is favored under normal conditions.G)Scheme of the 50-phosphotyrosine covalent bond in the Top2cc.It is thought that length or integrity of chromosome end is used as a mitotic counting mechanism in vitro 核酸代核酸代谢u物物质代代谢及及酶的的变化化端粒端粒酶Each mammalian chromosome end has a distinctive DNA-protein structure,which prevents the degradation and fusion of chromosome ends by helping distinguish chromosome ends from a double strand break in the genomic DNA.Mammalianhaveastretchofasimplerepeatsequenceunit(TTAGGG)andin,lengthis1520kb.Fiftyto200bpofthetelomericDNAshortensateachroundofmitosis.WhenaverageDNAreachesacriticallyshortlength,about47kb,isarrestedIrreversibly.核酸代核酸代谢端粒端粒酶u物物质代代谢及及酶的的变化化.u物物质代代谢及及酶的的变化化核酸代核酸代谢蛋白蛋白质代代谢糖代糖代谢酶系系统.u物物质代代谢及及酶的的变化化酶系系统增殖相关和分化相关的增殖相关和分化相关的酶转化相关和演化相关和演进相关的相关的酶细胞胞恶变的指的指标。主要正常主要正常细胞胞发生生转化，化，总可出可出现这类酶活性的活性的改改变。演演进相关的相关的酶 酶活性于活性于恶性程度呈平行关系的性程度呈平行关系的酶转化相关化相关.u肿瘤瘤细胞的分化胞的分化各种不同各种不同类型型细胞胞(分化分化细胞胞)同一来源的同一来源的幼稚幼稚细胞胞?分化的概念分化的概念特定的生理功能特定的生理功能特定的生化特征特定的生化特征特定的形特定的形态结构构.稳定性定性全能性全能性选择性性条件可逆性条件可逆性细胞分化特点胞分化特点:未分化未分化恶性性肿瘤是由于起源瘤是由于起源组织中的干中的干细胞胞丧失了分化的能力。失了分化的能力。.肿瘤瘤细胞分化异常的机制胞分化异常的机制遗传学改学改变信号信号转化异常化异常微微环境的影响境的影响诱导分化治分化治疗肿瘤瘤.u肿瘤瘤细胞的生胞的生长细胞增殖活性的原位胞增殖活性的原位检测方法及意方法及意义细胞增殖活性：胞增殖活性：细胞增生快慢的能力胞增生快慢的能力DNA DNA 含量含量测定定确定增生确定增生细胞的比例胞的比例DNA ploidy and proliferative activity as represented by the S-phase fraction(SPF).A link exists between high SPF values and increased risk of recurrence and death for patients with primary BC,Flow cytometry Flow cytometry 法法.u肿瘤瘤细胞的生胞的生长免疫免疫组织化学方法化学方法Several monoclonal antibodies reacting with different proliferating cell nuclear antigens have been described,such as PCNA,Ki-67 and MIB 1,KiS1 and others.The Ki-67/MIB 1 protein has a prognostic value for many types of malignant tumors.Ki-67OnlypaperspublishedinEnglishinpeerreviewedjournalsbeforeJune2004thatincludeatleast100evaluablepatientswereselected.Inaddition,theprognosticandpredictiveroleoftheproliferativemarkershadtobeassessedthroughmultivariateanalyses.Onehundredandthirty-twopapersfulfilledthesecriteriaand159516patientsanalyzed.u肿瘤瘤细胞的生胞的生长免疫免疫组织化学方法化学方法细胞周期蛋白胞周期蛋白The different cyclins：the concentration rise and fall at specific stages throughout the cell cycle,have a temporally distinct and highly regulated pattern of expression,i.e.they are synthesized and degraded at specific stages of the cell cycle.Cyclin E is the limiting factor for G1 phase progression and S phase entryRecently,severalsplicevariantsofcyclinE1,whicharenotpresentinnormalcells,havealsobeendiscovered;whichstimulatecellstoprogressthroughthecellcyclemuchmoreefficientlythanthefulllengthcyclinE1.Cyclin E was prognostic in seven out of 10 studies.u肿瘤瘤细胞的生胞的生长免疫免疫组织化学方法化学方法细胞周期蛋白胞周期蛋白The overexpression of cyclin E was accompanied by the appearance of low molecular weight(LMW)isoforms,and both were a reliable prognostic marker in stage IIII BC patients.High levels of cyclin E1 were predictive of resistance to tamoxifen adjuvant therapy in 108 node-positive BC patients,independently of ER status.Cyclin D1u肿瘤瘤细胞的生胞的生长细胞周期蛋白胞周期蛋白D-type cyclins are other key regulator proteins of the G1 phase progression.The protein is synthesized in response togrowth factors;its levels reach a maximum in the mid-G1phase of the cell cycle and then begin to drop.It appears that the association of cyclin D1 to Cdk is crucial to drive cells to the restriction point where the cell is committed to divide.A strong correlation between overexpression of cyclin D1 and HR-positivity has been reported in the majority of trials,but cyclin D1 does not appear to be a strong prognosticmarker.In fact,its overexpression has been associated with better RFS in only one studyCyclin D1u肿瘤瘤细胞的生胞的生长细胞周期蛋白胞周期蛋白.u肿瘤的生瘤的生长与与扩散散l肿瘤的瘤的扩散方式散方式直接蔓延直接蔓延转移移metastasismetastasis瘤瘤细胞从原胞从原发部位部位 侵入淋巴管、血管和体腔，侵入淋巴管、血管和体腔，扩散到其它部位，散到其它部位，形成与原形成与原发瘤瘤相同的相同的肿瘤。瘤。.转移移metastasismetastasisu肿瘤的生瘤的生长与与扩散散肿瘤的瘤的扩散方式散方式淋巴道淋巴道转移移Lymphatic metastasis is a predictor of poor Lymphatic metastasis is a predictor of poor outcome in many solid malignancies.outcome in many solid malignancies.The presence of lymph node metastases The presence of lymph node metastases decreases the 5-year survival of melanoma decreases the 5-year survival of melanoma patients independent of other prognostic patients independent of other prognostic factors of the primary tumor.factors of the primary tumor.Figure 1.DevelopmentoflymphaticvesselsinembryogenesisandcancerSomeoftheproteinsthatareimportantintheseeventsareshownunderneatheachsection.Arrowsdenotethedirectionoflymphflowinthelymphaticvessels.转移移metastasismetastasisu肿瘤的生瘤的生长与与扩散散肿瘤的瘤的扩散方式散方式血道血道转移移.转移移metastasismetastasisu肿瘤的生瘤的生长与与扩散散l肿瘤的瘤的扩散方式散方式种植性种植性转移移体腔内体腔内脏器的器的肿瘤蔓延至器官表面瘤蔓延至器官表面时，瘤瘤细胞可脱落种植于胞可脱落种植于体腔和各器官表面形成多数体腔和各器官表面形成多数转移瘤。移瘤。.u肿瘤瘤细胞胞扩散的散的过程机制程机制肿瘤侵瘤侵袭是是转移的前提；移的前提；侵侵袭和和转移的步移的步骤：脱离原脱离原发瘤群体瘤群体向周向周围组织浸浸润与局部血管或淋巴管密切接触，与局部血管或淋巴管密切接触，穿穿过其管壁其管壁穿透管壁，穿透管壁，在基在基质中增生中增生转移灶的形成和生移灶的形成和生长.u肿瘤瘤细胞胞扩散的散的过程机制程机制l细胞黏附与胞黏附与细胞黏附分子胞黏附分子侵侵袭和和转移的步移的步骤：脱离原脱离原发瘤群体瘤群体以配体核受体以配体核受体结合的形式，合的形式，使使细胞胞间发生粘生粘连integrin跨膜糖蛋白跨膜糖蛋白十六种十六种a a亚单位和位和8 8种种b b亚单位位.u肿瘤瘤细胞胞扩散的散的过程机制程机制l细胞黏附与胞黏附与细胞黏附分子胞黏附分子cadherin与与细胞骨架胞骨架连接接人人类至少有至少有1010多种多种钙粘蛋白粘蛋白E E；N N；P P.u肿瘤瘤细胞胞扩散的散的过程机制程机制l细胞黏附与胞黏附与细胞黏附分子胞黏附分子IgSF跨膜蛋白跨膜蛋白具有与具有与IgIg类似的似的结构构.u肿瘤瘤细胞胞扩散的散的过程机制程机制l细胞黏附与胞黏附与细胞黏附分子胞黏附分子Selectin familycancer cells adhere to by a process similar to that of LC homing.In this model,cells in flow are captured on the endothelial surface.transientadhesiveinteractionsbycellswithendothelialselectins(rolling),andfirmlyanchoredon(firmadhesion)toenableentryintotheunderlyingtissue.Theselectins,particularlyE-selectin,arerecognizedtomediateadhesionandthuspotentiateofcertaincancersu肿瘤瘤细胞胞扩散的散的过程机制程机制l细胞黏附与胞黏附与细胞黏附分子胞黏附分子Selectin family.u肿瘤瘤细胞胞扩散的散的过程机制程机制l细胞黏附与胞黏附与细胞黏附分子胞黏附分子CD44Atransmembraneprotein EssentialforthehomingandpropertiesofleukemicCells,CD44hasalsobeenfoundtosupportanchorage-independentgrowthinvitroandtumorgrowthandinexperimentalmodelsofsolidcancers.u肿瘤瘤细胞胞扩散的散的过程机制程机制肿瘤瘤细胞从原胞从原发灶分离的机制灶分离的机制肿瘤瘤细胞表面黏附分子减少。胞表面黏附分子减少。癌癌细胞胞钙含量降低含量降低恶性性肿瘤瘤细胞胞间连接接结构数量减少构数量减少肿瘤瘤细胞表面胞表面电荷增加荷增加.l肿瘤瘤细胞向周胞向周围组织的浸的浸润细胞外基胞外基质的降解的降解瘤瘤细胞的运胞的运动趋化因子的作用化因子的作用肿瘤血管生成瘤血管生成.肿瘤血管生成瘤血管生成l肿瘤瘤细胞向周胞向周围组织的浸的浸润.肿瘤血管生成瘤血管生成肿瘤瘤组织中微血管的来源中微血管的来源瘤瘤细胞生成的多种生胞生成的多种生长因子因子诱导瘤体生成微血管瘤体生成微血管残存于流体的宿主血管逐残存于流体的宿主血管逐渐变为肿瘤血管瘤血管VEGFVEGF是迄今是迄今鉴定出来的定出来的最重要的血管生成因子最重要的血管生成因子.Fig.1Switchingontheangiogenicphenotypeintumorsbygeneticandepigeneticfactors.Bothmalignantandnonmalignantcellsproducemultipleangiogenicfactorsandcytokinestoinducetumorneovascularization.Endogenousangiogenesisinhibitorsaredownregulatedtosupporttheangiogenicphenotype.肿瘤瘤细胞侵入血管和淋巴管胞侵入血管和淋巴管侵入血管和淋巴管侵入血管和淋巴管在循在循环中运行到达中运行到达远处部位部位Fig.1.SchematicdiagramshowinghowproductionofVEGF-CandVEGF-Cintumorscaninducelymphangiogenesis,leadingtoincreasedlymphaticvesseldensityinthevicinityofthetumor,andsubsequentlytometastasisofinvasivetumorcellsviathelymphvessels.Fig.1.l转移灶的形成和生移灶的形成和生长.u肿瘤侵瘤侵袭和和转移相关基因移相关基因Nm23Nm23基因基因NM23-H1 and NM23-H2 in humanNucleosidediphosphatekinases(NDPKs)catalyzetheexchangeof-phosphatebetweennucleoside(and2-deoxynucleoside)triphosphatesanddiphosphateswithformationofahigh-energyphosphohistidineintermediate(ParksandAgarwal1973).TheyareencodedbytheNMEgenes(alsoknownasNM23).参与参与调节细胞内微管系胞内微管系统的状的状态高度表达高度表达nm23nm23表表现为低低转移属性移属性.u肿瘤侵瘤侵袭和和转移相关基因移相关基因肿瘤瘤转移相关基因移相关基因mtal.u肿瘤侵瘤侵袭和和转移相关基因移相关基因Tiam1 基因基因鼠鼠T淋巴淋巴细胞瘤中克隆出来的基因。胞瘤中克隆出来的基因。产物具有物具有1591个氨基酸残基，个氨基酸残基，把蛋白把蛋白质锚定在定在质膜上膜上TIAM1 T-cell lymphoma invasion and metastasis 1 Homo sapiens ZhonghuaBingLiXueZaZhi.2009Apr;38(4):268-72.Overexpression of Tiam1 gene and its relationship with invasive and metastatic ability of nasopharyngeal carcinoma.Article in ChineseZhangXM,DingY,ChenJZ,JinH,YuLN,LiYF,DingYQ.Currently,manyGEFs,includingVav1,LARG,BcrandT-lymphomainvasionandmetastasis1(Tiam1),havebeenidentifiedasoncogenes.RESULTS:Tiam1 over expression significantly increased the abilities of adhesion,migratory and invasion of C666-1 and CNE1 cells,comparing with that of the control untransfected cells(P 0.05).CONCLUSION:Tiam1 expression correlates with the invasion and metastasis of nasopharyngeal carcinoma cells.u肿瘤侵瘤侵袭和和转移相关基因移相关基因Tiam1 基因基因鼠鼠T淋巴淋巴细胞瘤中克隆出来的基因。胞瘤中克隆出来的基因。.Overexpression of Tiam1 in hepatocellular carcinomas predicts poor prognosis of HCC patientsYi Ding1,Bin Chen2,Shuang Wang3,Liang Zhao3,Juanzhi Chen3,Yanqing Ding3,Longhua Chen1*and Rongcheng Luo2*Int.J.Cancer:124,653658(2009)2008 Wiley-Liss,Inc.u肿瘤侵瘤侵袭和和转移相关基因移相关基因Tiam1 基因基因 鼠鼠T淋巴淋巴细胞瘤中克隆出来的基因。胞瘤中克隆出来的基因。.生生长因子通因子通过Ras信号通路，信号通路，导致致细胞增殖。胞增殖。转染染给NIH3T3细胞，胞，引起大量侵引起大量侵袭和和转移。移。Activated KrasG12D is associated with invasion and metastasis of pancreatic cancer cells through inhibition of E-cadherinBritish Journal of Cancer 104,1038-1048(15 March 2011)S Rachagani,S Senapati,S Chakraborty,M P Ponnusamy,S Kumar,L M Smith,M Jain and S K Batra u肿瘤侵瘤侵袭和和转移相关基因移相关基因Ras 基因基因包括包括H-ras，K-ras 和和N-ras 三三类，.Results:TheKrasG12Dknockdowncellsexhibitedasignificantdecreaseinmotility(P0.0001),invasion(P0.0001),anchorage-dependent(P0.0001)andanchorage-independentgrowth(P0.0001),proliferation(P0.005)andanincreaseincelldoublingtime(P0.005)invitroandadecreaseintheincidenceofmetastasesuponorthotopicimplantationintonudemice.TheknockdownoftheKrasG12DalleleledtoasignificantincreaseintheexpressionofE-cadherin(mRNAandprotein)bothinvitroandinvivo.Thiswasassociatedwithadecreaseintheexpressionofphoshpo-ERK-1/2,NF-B and MMP-9,and transcription factors such as EF1,Snail and ETV4.Furthermore,the expression of several proteins involved in cell survival,invasion and metastasis was decreased in the KrasG12Dknockdowncells.Conclusions:TheresultsofthisstudysuggestthattheKrasG12DallelepromotesmetastasisinPCcellspartlythroughthedownregulationofE-cadherin.u肿瘤侵瘤侵袭和和转移相关基因移相关基因Ras 基因基因包括包括H-ras，K-ras 和和N-ras 三三类，British Journal of Cancer 104,1038-1048(15 March 2011).The EndThe End！.