肿瘤的生物学特性(高级教育)课件

肿瘤的生物化学特性1 1经验课堂经验课堂肿瘤的生物化学特性1经验课堂n物质代谢及酶的变化物质代谢及酶的变化n肿瘤细胞的分化肿瘤细胞的分化n肿瘤细胞的生长肿瘤细胞的生长n肿瘤细胞扩散的过程机制肿瘤细胞扩散的过程机制n肿瘤侵袭和转移相关基因肿瘤侵袭和转移相关基因2 2经验课堂经验课堂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3 3经验课堂经验课堂3经验课堂n核酸代谢核酸代谢n核酸增多是肿瘤迅速生长的物质基础核酸增多是肿瘤迅速生长的物质基础nDNADNA拓扑异构酶拓扑异构酶n物质代谢及酶的变化物质代谢及酶的变化n端粒酶端粒酶4 4经验课堂经验课堂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nDNADNA拓扑异构酶拓扑异构酶n存在于细胞核内的一类酶，他们能够催化存在于细胞核内的一类酶，他们能够催化存在于细胞核内的一类酶，他们能够催化存在于细胞核内的一类酶，他们能够催化DNADNADNADNA链的链的链的链的断裂和结合，从而控制断裂和结合，从而控制断裂和结合，从而控制断裂和结合，从而控制DNADNADNADNA的拓扑状态。的拓扑状态。的拓扑状态。的拓扑状态。nDNADNADNADNA拓扑异构酶通过形成短暂的单链裂解拓扑异构酶通过形成短暂的单链裂解拓扑异构酶通过形成短暂的单链裂解拓扑异构酶通过形成短暂的单链裂解-结合循环，结合循环，结合循环，结合循环，催化催化催化催化DNADNADNADNA复制复制复制复制的拓扑异构状态的变化的拓扑异构状态的变化的拓扑异构状态的变化的拓扑异构状态的变化 n核酸代谢核酸代谢n物质代谢及酶的变化物质代谢及酶的变化5 5经验课堂经验课堂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(A)Classification of human DNA topoisomerases.Type IB are the only(A)Classification of human DNA topoisomerases.Type IB are the only enzymes that form cleavage complexes(cc)with 30-phosphotyrosyl(30-P-Y)enzymes that form cleavage complexes(cc)with 30-phosphotyrosyl(30-P-Y)intermediates.intermediates.(C)Noncovalent binding of type IB enzymes.(D)Scheme of the 30(C)Noncovalent binding of type IB enzymes.(D)Scheme of the 30 phosphotyrosine covalent bond in the Top1cc.The arrow indicates the phosphotyrosine covalent bond in the Top1cc.The arrow indicates the reversible(religation)reaction,which is favored under normal conditions.G)reversible(religation)reaction,which is favored under normal conditions.G)Scheme of the 50-phosphotyrosine covalent bond in the Top2cc.Scheme of the 50-phosphotyrosine covalent bond in the Top2cc.6 6经验课堂经验课堂(A)Classification of human DN7 7经验课堂经验课堂7经验课堂It is thought that length or integrity of chromosome It is thought that length or integrity of chromosome end is used as a mitotic counting mechanism end is used as a mitotic counting mechanism in vitro in vitro n核酸代谢核酸代谢n物质代谢及酶的变化物质代谢及酶的变化n端粒酶端粒酶Each mammalian chromosome end has a Each mammalian chromosome end has a distinctive DNA-protein structure,which prevents distinctive DNA-protein structure,which prevents the degradation and fusion of chromosome ends the degradation and fusion of chromosome ends by helping distinguish chromosome ends from a by helping distinguish chromosome ends from a double strand break in the genomic DNA.double strand break in the genomic DNA.8 8经验课堂经验课堂It is thought that length or MammalianhaveastretchofasimplerepeatsequenceMammalianhaveastretchofasimplerepeatsequenceunit(TTAGGG)andin,lengthis1520kb.unit(TTAGGG)andin,lengthis1520kb.Fiftyto200bpofthetelomericDNAshortensateachFiftyto200bpofthetelomericDNAshortensateachroundofmitosis.WhenaverageDNAreachesaroundofmitosis.WhenaverageDNAreachesacriticallyshortlength,about47kb,isarrestedcriticallyshortlength,about47kb,isarrestedIrreversibly.Irreversibly.n核酸代谢核酸代谢n端粒酶端粒酶n物质代谢及酶的变化物质代谢及酶的变化9 9经验课堂经验课堂Mammalian have a stretch of an物质代谢及酶的变化物质代谢及酶的变化n核酸代谢核酸代谢n蛋白质代谢蛋白质代谢n糖代谢糖代谢n酶系统酶系统1010经验课堂经验课堂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经验课堂n物质代谢及酶的变化物质代谢及酶的变化n酶系统酶系统n增殖相关和分化相关的酶增殖相关和分化相关的酶n转化相关和演进相关的酶转化相关和演进相关的酶细胞恶变的指标。细胞恶变的指标。细胞恶变的指标。细胞恶变的指标。主要正常细胞发生转化，主要正常细胞发生转化，主要正常细胞发生转化，主要正常细胞发生转化，总可出现这类酶活性的总可出现这类酶活性的总可出现这类酶活性的总可出现这类酶活性的改变。改变。改变。改变。演进相关的酶演进相关的酶演进相关的酶演进相关的酶 酶活性于恶性程度呈平行关系的酶酶活性于恶性程度呈平行关系的酶酶活性于恶性程度呈平行关系的酶酶活性于恶性程度呈平行关系的酶转化相关转化相关转化相关转化相关1111经验课堂经验课堂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n肿瘤细胞的分化肿瘤细胞的分化各种不同各种不同各种不同各种不同类型细胞类型细胞类型细胞类型细胞(分化细胞分化细胞分化细胞分化细胞)同一来源的同一来源的同一来源的同一来源的幼稚细胞幼稚细胞幼稚细胞幼稚细胞?n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生化特征特定的生化特征特定的形态结构特定的形态结构特定的形态结构特定的形态结构1212经验课堂经验课堂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n稳定性稳定性稳定性稳定性n全能性全能性全能性全能性n选择性选择性选择性选择性n条件可逆性条件可逆性条件可逆性条件可逆性n细胞分化特点细胞分化特点: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。丧失了分化的能力。1313经验课堂经验课堂稳定性细胞分化特点:未分化恶性肿瘤是由于起源组织中的干细胞1n肿瘤细胞分化异常的机制肿瘤细胞分化异常的机制n遗传学改变遗传学改变n信号转化异常信号转化异常n微环境的影响微环境的影响n诱导分化治疗肿瘤诱导分化治疗肿瘤1414经验课堂经验课堂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n肿瘤细胞的生长肿瘤细胞的生长n细胞增殖活性的原位检测方法及意义细胞增殖活性的原位检测方法及意义细胞增殖活性：细胞增殖活性：细胞增生快慢的能力细胞增生快慢的能力DNA DNA 含量测定含量测定确定增生细胞的比例确定增生细胞的比例DNA ploidy and proliferative activity as DNA ploidy and proliferative activity as represented by the S-phase fraction(SPF).represented by the S-phase fraction(SPF).A link exists between high SPF values and A link exists between high SPF values and increased risk of recurrence and death for increased risk of recurrence and death for patients with primary BC,patients with primary BC,Flow cytometry Flow cytometry 法法1515经验课堂经验课堂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：n肿瘤细胞的生长肿瘤细胞的生长n免疫组织化学方法免疫组织化学方法Several monoclonal antibodies reacting with Several monoclonal antibodies reacting with different proliferating cell nuclear antigens have different proliferating cell nuclear antigens have been described,such as PCNA,Ki-67 and MIB 1,been described,such as PCNA,Ki-67 and MIB 1,KiS1 and others.KiS1 and others.The Ki-67/MIB 1 protein has a The Ki-67/MIB 1 protein has a prognostic valueprognostic value for many types of malignant tumors.for many types of malignant tumors.nKi-67OnlypaperspublishedinEnglishinpeerreviewedjournalsbeforeJuneOnlypaperspublishedinEnglishinpeerreviewedjournalsbeforeJune2004that2004thatincludeatleast100evaluablepatientsincludeatleast100evaluablepatientswereselected.Inwereselected.Inaddition,theaddition,theprognosticandpredictiveroleoftheproliferativemarkersprognosticandpredictiveroleoftheproliferativemarkershadtobeassessedthroughmultivariateanalyseshadtobeassessedthroughmultivariateanalyses.OnehundredandOnehundredandthirty-twopapersthirty-twopapersfulfilledthesecriteriaandfulfilledthesecriteriaand159516159516patientspatientsanalyzed.analyzed.1616经验课堂经验课堂肿瘤细胞的生长免疫组织化学方法Several monoclon肿瘤细胞的生长肿瘤细胞的生长n免疫组织化学方法免疫组织化学方法n细胞周期蛋白细胞周期蛋白The different cyclinsThe different cyclins：the concentration rise and the concentration rise and fall at specific stages throughout the cell cycle,fall at specific stages throughout the cell cycle,have a have a temporally distincttemporally distinct and and highly regulated highly regulated pattern of expressionpattern of expression,i.e.they are synthesized and,i.e.they are synthesized and degraded at specific stages of the cell cycle.degraded at specific stages of the cell cycle.Cyclin E is the limiting factor for G1 phase Cyclin E is the limiting factor for G1 phase progression and S phase entryprogression and S phase entryRecently,severalsplicevariantsofcyclinE1,whichRecently,severalsplicevariantsofcyclinE1,whicharenotpresentinnormalcells,havealsobeenarenotpresentinnormalcells,havealsobeendiscovered;discovered;whichstimulatecellstoprogressthroughthecellwhichstimulatecellstoprogressthroughthecellcyclemuchmoreefficientlythanthefulllengthcyclinE1cyclemuchmoreefficientlythanthefulllengthcyclinE11717经验课堂经验课堂肿瘤细胞的生长免疫组织化学方法细胞周期蛋白The diffeCyclin E was prognostic in seven out of 10 Cyclin E was prognostic in seven out of 10 studies.studies.n肿瘤细胞的生长肿瘤细胞的生长n免疫组织化学方法免疫组织化学方法n细胞周期蛋白细胞周期蛋白The overexpression of cyclin E was accompanied by The overexpression of cyclin E was accompanied by the appearance of low molecular weight(LMW)the appearance of low molecular weight(LMW)isoforms,and both were a reliable prognostic marker isoforms,and both were a reliable prognostic marker in stage IIII BC patients.in stage IIII BC patients.High levels of cyclin E1 were predictive of High levels of cyclin E1 were predictive of resistance to tamoxifen adjuvant therapy in 108 resistance to tamoxifen adjuvant therapy in 108 node-positive BC patients,independently of ER node-positive BC patients,independently of ER status.status.1818经验课堂经验课堂Cyclin E was prognostic in sevnCyclin D1Cyclin D1n肿瘤细胞的生长肿瘤细胞的生长n细胞周期蛋白细胞周期蛋白D-type cyclins are other key regulator proteins D-type cyclins are other key regulator proteins of the G1 phase progression.of the G1 phase progression.The protein is synthesized in response toThe protein is synthesized in response togrowth factors;its levels reach a maximum in the growth factors;its levels reach a maximum in the mid-G1phase of the cell cycle and then begin to mid-G1phase of the cell cycle and then begin to drop.It appears that the association of cyclin D1 drop.It appears that the association of cyclin D1 to Cdk is crucial to drive cells to the restriction to Cdk is crucial to drive cells to the restriction point where the cell is committed to dividepoint where the cell is committed to divide1919经验课堂经验课堂Cyclin D1肿瘤细胞的生长细胞周期蛋白D-type cA strong correlation between overexpression A strong correlation between overexpression of cyclin D1 and HR-positivity has been of cyclin D1 and HR-positivity has been reported in the majority of trials,but cyclin D1 reported in the majority of trials,but cyclin D1 does not appear to be a strong prognosticdoes not appear to be a strong prognosticmarker.In fact,its overexpression has been marker.In fact,its overexpression has been associated with better RFS in only one studyassociated with better RFS in only one studynCyclin D1Cyclin D1n肿瘤细胞的生长肿瘤细胞的生长n细胞周期蛋白细胞周期蛋白2020经验课堂经验课堂A strong correlation between on肿瘤的生长与扩散肿瘤的生长与扩散n肿瘤的扩散方式肿瘤的扩散方式n直接蔓延直接蔓延n转移转移metastasismetastasisn瘤细胞从原发部位瘤细胞从原发部位瘤细胞从原发部位瘤细胞从原发部位 侵入淋巴管、血管和体腔，侵入淋巴管、血管和体腔，侵入淋巴管、血管和体腔，侵入淋巴管、血管和体腔，n扩散到其它部位，扩散到其它部位，扩散到其它部位，扩散到其它部位，形成与原发瘤形成与原发瘤形成与原发瘤形成与原发瘤相同的肿瘤。相同的肿瘤。相同的肿瘤。相同的肿瘤。2121经验课堂经验课堂肿瘤的生长与扩散肿瘤的扩散方式直接蔓延转移metastasin转移转移nmetastasismetastasisn肿瘤的生长与扩散肿瘤的生长与扩散n肿瘤的扩散方式肿瘤的扩散方式n淋巴道转移淋巴道转移Lymphatic metastasis is a predictor of poor Lymphatic metastasis is a predictor of poor Lymphatic metastasis is a predictor of poor Lymphatic metastasis is a predictor of poor outcome in many solid malignancies.outcome in many solid malignancies.outcome in many solid malignancies.outcome in many solid malignancies.The presence of lymph node metastases The presence of lymph node metastases 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 decreases the 5-year survival of melanoma decreases the 5-year survival of melanoma patients independent of other prognostic patients independent of other prognostic patients independent of other prognostic patients independent of other prognostic factors of the primary tumor.factors of the primary tumor.factors of the primary tumor.factors of the primary tumor.2222经验课堂经验课堂转移metastasis肿瘤的生长与扩散肿瘤的扩散方式淋巴道Figure 1.Figure 1.DevelopmentofDevelopmentoflymphaticvesselsinlymphaticvesselsinembryogenesisandcancerembryogenesisandcancerSomeoftheproteinsthatareSomeoftheproteinsthatareimportantintheseimportantintheseeventsareshownunderneatheventsareshownunderneatheachsection.eachsection.ArrowsdenotethedirectionofArrowsdenotethedirectionoflymphflowinthelymphflowinthelymphaticvessels.lymphaticvessels.2323经验课堂经验课堂Figure 1.Development of lympn转移转移metastasismetastasisn肿瘤的生长与扩散肿瘤的生长与扩散n肿瘤的扩散方式肿瘤的扩散方式n血道转移血道转移2424经验课堂经验课堂转移metastasis肿瘤的生长与扩散肿瘤的扩散方式血道转n转移转移metastasismetastasisn肿瘤的生长与扩散肿瘤的生长与扩散n肿瘤的扩散方式肿瘤的扩散方式n种植性转移种植性转移体腔内脏器的肿瘤蔓延至器官表面时，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瘤细胞可脱落种植于体腔和各器官表面形成多数转移瘤。体腔和各器官表面形成多数转移瘤。2525经验课堂经验课堂转移metastasis肿瘤的生长与扩散肿瘤的扩散方式种植性n肿瘤细胞扩散的过程机制肿瘤细胞扩散的过程机制n肿瘤侵袭是转移的前提；肿瘤侵袭是转移的前提；n侵袭和转移的步骤：侵袭和转移的步骤：n脱离原发瘤群体脱离原发瘤群体n向周围组织浸润向周围组织浸润n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，穿过穿过其管壁其管壁n穿透管壁，穿透管壁，在基质中增生在基质中增生n转移灶的形成和生长转移灶的形成和生长2626经验课堂经验课堂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n肿瘤细胞扩散的过程机制肿瘤细胞扩散的过程机制n细胞黏附与细胞黏附分子细胞黏附与细胞黏附分子n侵袭和转移的步骤：侵袭和转移的步骤：n脱离原发瘤群体脱离原发瘤群体n以配体核受体结合的形式，以配体核受体结合的形式，以配体核受体结合的形式，以配体核受体结合的形式，使细胞间发生粘连使细胞间发生粘连使细胞间发生粘连使细胞间发生粘连nintegrinn跨膜糖蛋白跨膜糖蛋白跨膜糖蛋白跨膜糖蛋白n十六种十六种十六种十六种a a a a亚单位和亚单位和亚单位和亚单位和8 8 8 8种种种种b b b b亚单位亚单位亚单位亚单位2727经验课堂经验课堂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n肿瘤细胞扩散的过程机制肿瘤细胞扩散的过程机制n细胞黏附与细胞黏附分子细胞黏附与细胞黏附分子ncadherinn与细胞骨架连接与细胞骨架连接n人类至少有人类至少有1010多种钙粘蛋白多种钙粘蛋白E E；N N；P P2828经验课堂经验课堂肿瘤细胞扩散的过程机制细胞黏附与细胞黏附分子cadherinn肿瘤细胞扩散的过程机制肿瘤细胞扩散的过程机制n细胞黏附与细胞黏附分子细胞黏附与细胞黏附分子nIgSFn跨膜蛋白跨膜蛋白n具有与具有与IgIg类似的结构类似的结构2929经验课堂经验课堂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n肿瘤细胞扩散的过程机制肿瘤细胞扩散的过程机制n细胞黏附与细胞黏附分子细胞黏附与细胞黏附分子nSelectin familycancer cells adhere to by a process similar to cancer cells adhere to by a process similar to that of LC homing.In this model,cells in flow that of LC homing.In this model,cells in flow are captured on the endothelial surface.are captured on the endothelial surface.3030经验课堂经验课堂肿瘤细胞扩散的过程机制细胞黏附与细胞黏附分子Selectintransientadhesiveinteractionsbycellswithendothelialtransientadhesiveinteractionsbycellswithendothelialselectins(rolling),andfirmlyanchoredon(firmadhesion)selectins(rolling),andfirmlyanchoredon(firmadhesion)toenableentryintotheunderlyingtissue.Theselectins,toenableentryintotheunderlyingtissue.Theselectins,particularlyE-selectin,arerecognizedtomediateparticularlyE-selectin,arerecognizedtomediateadhesionandthuspotentiateofcertaincancersadhesionandthuspotentiateofcertaincancersn肿瘤细胞扩散的过程机制肿瘤细胞扩散的过程机制n细胞黏附与细胞黏附分子细胞黏附与细胞黏附分子nSelectin family3131经验课堂经验课堂transient adhesive interactionn肿瘤细胞扩散的过程机制肿瘤细胞扩散的过程机制n细胞黏附与细胞黏附分子细胞黏附与细胞黏附分子nCD44nAtransmembraneproteinAtransmembraneprotein nEssentialforthehomingandpropertiesofleukemicEssentialforthehomingandpropertiesofleukemicCells,Cells,nCD44hasalsobeenfoundtosupportanchorage-CD44hasalsobeenfoundtosupportanchorage-independentgrowthinvitroandtumorgrowthandindependentgrowthinvitroandtumorgrowthandinexperimentalmodelsofsolidcancersinexperimentalmodelsofsolidcancers 3232经验课堂经验课堂肿瘤细胞扩散的过程机制细胞黏附与细胞黏附分子CD44A trn肿瘤细胞扩散的过程机制肿瘤细胞扩散的过程机制n肿瘤细胞从原发灶分离的机制肿瘤细胞从原发灶分离的机制n肿瘤细胞表面黏附分子减少。肿瘤细胞表面黏附分子减少。n癌细胞钙含量降低癌细胞钙含量降低n恶性肿瘤细胞间连接结构数量减少恶性肿瘤细胞间连接结构数量减少n肿瘤细胞表面电荷增加肿瘤细胞表面电荷增加3333经验课堂经验课堂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n肿瘤细胞向周围组织的浸润肿瘤细胞向周围组织的浸润n细胞外基质的降解细胞外基质的降解n瘤细胞的运动瘤细胞的运动n趋化因子的作用趋化因子的作用n肿瘤血管生成肿瘤血管生成3434经验课堂经验课堂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n肿瘤血管生成肿瘤血管生成n肿瘤细胞向周围组织的浸润肿瘤细胞向周围组织的浸润3535经验课堂经验课堂肿瘤血管生成肿瘤细胞向周围组织的浸润35经验课堂n肿瘤血管生成肿瘤血管生成n肿瘤组织中微血管的来源肿瘤组织中微血管的来源肿瘤组织中微血管的来源肿瘤组织中微血管的来源n瘤细胞生成的多种生长因子瘤细胞生成的多种生长因子瘤细胞生成的多种生长因子瘤细胞生成的多种生长因子n诱导瘤体生成微血管诱导瘤体生成微血管诱导瘤体生成微血管诱导瘤体生成微血管n残存于流体的宿主血管逐渐残存于流体的宿主血管逐渐残存于流体的宿主血管逐渐残存于流体的宿主血管逐渐变为肿瘤血管变为肿瘤血管变为肿瘤血管变为肿瘤血管nVEGFVEGFVEGFVEGF是迄今鉴定出来的是迄今鉴定出来的是迄今鉴定出来的是迄今鉴定出来的最重要的血管生成因子最重要的血管生成因子最重要的血管生成因子最重要的血管生成因子3636经验课堂经验课堂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Fig.1SwitchingontheangiogenicphenotypeintumorsbyFig.1Switchingontheangiogenicphenotypeintumorsbygeneticandepigeneticfactors.Bothmalignantandnonmalignantgeneticandepigeneticfactors.Bothmalignantandnonmalignantcellsproducemultipleangiogenicfactorsandcytokinestoinducecellsproducemultipleangiogenicfactorsandcytokinestoinducetumorneovascularization.Endogenousangiogenesisinhibitorstumorneovascularization.Endogenousangiogenesisinhibitorsaredownregulatedtosupporttheangiogenicphenotypearedownregulatedtosupporttheangiogenicphenotype3737经验课堂经验课堂Fig.1 Switching on the angiogn肿瘤细胞侵入血管和淋巴管肿瘤细胞侵入血管和淋巴管n侵入血管和淋巴管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环中运行到达远处部位在循环中运行到达远处部位在循环中运行到达远处部位在循环中运行到达远处部位Fig.1.SchematicdiagramshowinghowproductionofVEGF-CandVEGF-CintumorsFig.1.SchematicdiagramshowinghowproductionofVEGF-CandVEGF-Cintumorscaninducelymphangiogenesis,leadingtoincreasedlymphaticvesseldensityinthecaninducelymphangiogenesis,leadingtoincreasedlymphaticvesseldensityinthevicinityofthetumor,andsubsequentlytometastasisofinvasivetumorcellsviathevicinityofthetumor,andsubsequentlytometastasisofinvasivetumorcellsviathelymphvessels.lymphvessels.Fig.1.Fig.1.3838经验课堂经验课堂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n转移灶的形成和生长转移灶的形成和生长3939经验课堂经验课堂转移灶的形成和生长39经验课堂n肿瘤侵袭和转移相关基因肿瘤侵袭和转移相关基因nNm23Nm23基因基因NM23-H1 and NM23-H2 in humanNucleosidediphosphatekinases(NDPKs)catalyzetheNucleosidediphosphatekinases(NDPKs)catalyzetheexchangeof-phosphatebetweennucleoside(and2-exchangeof-phosphatebetweennucleoside(and2-deoxynucleoside)triphosphatesanddiphosphateswithdeoxynucleoside)triphosphatesanddiphosphateswithformationofahigh-energyphosphohistidineintermediateformationofahigh-energyphosphohistidineintermediate(ParksandAgarwal1973).TheyareencodedbytheNME(ParksandAgarwal1973).TheyareencodedbytheNMEgenes(alsoknownasNM23).genes(alsoknownasNM23).n参与调节细胞内微管系统的状态参与调节细胞内微管系统的状态参与调节细胞内微管系统的状态参与调节细胞内微管系统的状态n高度表达高度表达高度表达高度表达nm23nm23nm23nm23表现为低转移属性表现为低转移属性表现为低转移属性表现为低转移属性4040经验课堂经验课堂肿瘤侵袭和转移相关基因Nm23基因NM23-H1 and Nn肿瘤侵袭和转移相关基因肿瘤侵袭和转移相关基因n肿瘤转移相关基因肿瘤转移相关基因mtal4141经验课堂经验课堂肿瘤侵袭和转移相关基因肿瘤转移相关基因mtal41经验课堂n肿瘤侵袭和转移相关基因肿瘤侵袭和转移相关基因nTiam1 Tiam1 基因基因基因基因鼠鼠鼠鼠T T淋巴细胞瘤中克隆出来的基因。淋巴细胞瘤中克隆出来的基因。淋巴细胞瘤中克隆出来的基因。淋巴细胞瘤中克隆出来的基因。产物具有产物具有产物具有产物具有15911591个氨基酸残基，个氨基酸残基，个氨基酸残基，个氨基酸残基，把蛋白质锚定在质膜上把蛋白质锚定在质膜上把蛋白质锚定在质膜上把蛋白质锚定在质膜上TIAM1TIAM1 T-cell lymphoma invasion and metastasis 1 Homo sapiens T-cell lymphoma invasion and metastasis 1 Homo sapiens ZhonghuaBingLiXueZaZhi.2009Apr;38(4):268-72.ZhonghuaBingLiXueZaZhi.2009Apr;38(4):268-72.Overexpression of Tiam1 gene and its relationship with invasive and metastatic Overexpression of Tiam1 gene and its relationship with invasive and metastatic ability of nasopharyngeal carcinoma.ability of nasopharyngeal carcinoma.Article in ChineseArticle in ChineseZhangXMZhangXM,DingYDingY,ChenJZChenJZ,JinHJinH,YuLNYuLN,LiYFLiYF,DingYQDingYQ.Currently,manyGEFs,includingVav1,LARG,BcrandT-lymphomainvasionandCurrently,manyGEFs,includingVav1,LARG,BcrandT-lymphomainvasionandmetastasis1(Tiam1),havebeenidentifiedasoncogenes.metastasis1(Tiam1),havebeenidentifiedasoncogenes.4242经验课堂经验课堂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RESULTS:RESULTS:Tiam1 over expression significantly increased the abilities of Tiam1 over expression significantly increased the abilities of adhesion,migratory and invasion of C666-1 and CNE1 cells,adhesion,migratory and invasion of C666-1 and CNE1 cells,comparing with that of the control untransfected cells comparing with that of the control untransfected cells(P 0.05).(P 0.05).CONCLUSION:CONCLUSION:Tiam1 expression correlates with the invasion and metastasis Tiam1 expression correlates with the invasion and metastasis of nasopharyngeal carcinoma cells.of nasopharyngeal carcinoma cells.n肿瘤侵袭和转移相关基因肿瘤侵袭和转移相关基因nTiam1 Tiam1 基因基因基因基因鼠鼠鼠鼠T T淋巴细胞瘤中克隆出来的基因。淋巴细胞瘤中克隆出来的基因。淋巴细胞瘤中克隆出来的基因。淋巴细胞瘤中克隆出来的基因。4343经验课堂经验课堂RESULTS:肿瘤侵袭和转移相关基因Tiam1 基因鼠TOverexpression of Tiam1 in hepatocellular carcinomas Overexpression of Tiam1 in hepatocellular carcinomas predicts poor prognosis of HCC patientspredicts poor prognosis of HCC patientsYi Ding1,Bin Chen2,Shuang Wang3,Liang Zhao3,Yi Ding1,Bin Chen2,Shuang Wang3,Liang Zhao3,Juanzhi Chen3,Yanqing Ding3,Longhua Chen1*and Juanzhi Chen3,Yanqing Ding3,Longhua Chen1*and Rongcheng Luo2*Rongcheng Luo2*Int.J.Cancer:124,653658 Int.J.Cancer:124,653658(2009)(2009)2008 Wiley-Liss,Inc.2008 Wiley-Liss,Inc.n肿瘤侵袭和转移相关基因肿瘤侵袭和转移相关基因nTiam1 Tiam1 基因基因基因基因 鼠鼠鼠鼠T T淋巴细胞瘤中克隆出来的基因。淋巴细胞瘤中克隆出来的基因。淋巴细胞瘤中克隆出来的基因。淋巴细胞瘤中克隆出来的基因。4444经验课堂经验课堂Overexpression of Tiam1 in hep生长因子通过生长因子通过生长因子通过生长因子通过RasRas信号通路，信号通路，信号通路，信号通路，导致细胞增殖。导致细胞增殖。导致细胞增殖。导致细胞增殖。转染给转染给转染给转染给NIH3T3NIH3T3细胞，细胞，细胞，细胞，引起大量侵袭和转移。引起大量侵袭和转移。引起大量侵袭和转移。引起大量侵袭和转移。Activated KrasActivated KrasG12DG12D is associated with invasion and metastasis is associated with invasion and metastasis of pancreatic cancer cells through inhibition of E-cadherinof pancreatic cancer cells through inhibition of E-cadherinBritish Journal of CancerBritish Journal of Cancer 104,1038-1048(15 March 2011)104,1038-1048(15 March 2011)S Rachagani,S Senapati,S Chakraborty,M P Ponnusamy,S Kumar,S Rachagani,S Senapati,S Chakraborty,M P Ponnusamy,S Kumar,L M Smith,M Jain and S K Batra L M Smith,M Jain and S K Batra n肿瘤侵袭和转移相关基因肿瘤侵袭和转移相关基因nRas Ras 基因基因基因基因包括包括包括包括H-rasH-ras，K-ras K-ras 和和和和N-ras N-ras 三类，三类，三类，三类，4545经验课堂经验课堂生长因子通过Ras信号通路，导致细胞增殖。转染给NIHResults:Results:TheKrasG12Dknockdowncellsexhibitedasignificantdecreaseinmotility(P0.0001),TheKrasG12Dknockdowncellsexhibitedasignificantdecreaseinmotility(P0.0001),invasion(P0.0001),anchorage-dependent(P0.0001)andanchorage-independentinvasion(P0.0001),anchorage-dependent(P0.0001)andanchorage-independentgrowth(P0.0001),proliferation(P0.005)andanincreaseincelldoublingtime(P0.005)growth(P0.0001),proliferation(P0.005)andanincreaseincelldoublingtime(P0.005)invitroandadecreaseintheincidenceofmetastasesuponorthotopicimplantationintoinvitroandadecreaseintheincidenceofmetastasesuponorthotopicimplantationintonudemice.TheknockdownoftheKrasG12Dalleleledtoasignificantincreaseinthenudemice.TheknockdownoftheKrasG12DalleleledtoasignificantincreaseintheexpressionofE-cadherin(mRNAandprotein)bothinvitroandinvivo.ThiswasexpressionofE-cadherin(mRNAandprotein)bothinvitroandinvivo.Thiswasassoc