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1、关于肿瘤的生物学特性第一页，本课件共有47页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第二页，本课件共有47页第三页，本课件共有47页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端粒酶端粒酶第四页，本课件共有47页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DNADNA链的
2、链的断裂和结合，从而控制断裂和结合，从而控制DNADNA的拓扑状态。的拓扑状态。nDNADNA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，催化催化DNADNA复制复制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第五页，本课件共有47页(A)Classification of human DNA topoisomerases.Type IB are the only enzymes that form cleavage complexes(cc)with 30-phosphotyrosyl(30-P-
3、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.第六页，本课件共有47页第七页，本课件
4、共有47页It is thought that length or integrity of chromosome end is used as a mitotic counting mechanism 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 distinctive DNA-protein structure,which prevents the degradation and fusion of chromosome ends by helping distinguish
5、chromosome ends from a double strand break in the genomic DNA.第八页，本课件共有47页Mammalianhaveastretchofasimplerepeatsequenceunit(TTAGGG)andin,lengthis1520kb.Fiftyto200bpofthetelomericDNAshortensateachroundofmitosis.WhenaverageDNAreachesacriticallyshortlength,about47kb,isarrestedIrreversibly.n核酸代谢核酸代谢n端粒酶端
6、粒酶n物质代谢及酶的变化物质代谢及酶的变化第九页，本课件共有47页n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酶系统酶系统第十页，本课件共有47页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。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改变。改变。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转化相关转化相关第十一页，本课件共有47页n肿瘤
7、细胞的分化肿瘤细胞的分化各种不同各种不同类型细胞类型细胞(分化细胞分化细胞)同一来源的幼同一来源的幼稚细胞稚细胞?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化特征特定的生化特征特定的形态结构特定的形态结构第十二页，本课件共有47页n稳定性稳定性n全能性全能性n选择性选择性n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。第十三页，本课件共有47页n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
8、导分化治疗肿瘤诱导分化治疗肿瘤第十四页，本课件共有47页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 represented by the S-phase fraction(SPF).A link exists between high SPF values and increased risk of recurrence and d
9、eath for patients with primary BC,Flow cytometry Flow cytometry 法法第十五页，本课件共有47页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 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 prog
10、nostic value for many types of malignant tumors.nKi-67OnlypaperspublishedinEnglishinpeerreviewedjournalsbeforeJune2004thatincludeatleast100evaluablepatientswereselected.Inaddition,theprognosticandpredictiveroleoftheproliferativemarkershadtobeassessedthroughmultivariateanalyses.Onehundredandthirty-tw
11、opapersfulfilledthesecriteriaand159516patientsanalyzed.第十六页，本课件共有47页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 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 synth
12、esized 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;whichstimulatecellstoprogressthroughthecellcyclemuchmoreefficientlythanth
13、efulllengthcyclinE1第十七页，本课件共有47页Cyclin E was prognostic in seven out of 10 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 appearance of low molecular weight(LMW)isoforms,and both were a reliable prognostic marker in stage IIII BC patients.H
14、igh levels of cyclin E1 were predictive of resistance to tamoxifen adjuvant therapy in 108 node-positive BC patients,independently of ER status.第十八页，本课件共有47页nCyclin 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 of the G1 phase progression.The protein is synthesized in
15、 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第十九页，本课件共有47页A strong correlation between over
16、expression 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 studynCyclin 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第二十页，本课件共有47页n肿瘤的生长与扩散肿瘤的生长与扩散n肿瘤的
17、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 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，形成与原发瘤形成与原发瘤相同的肿瘤。相同的肿瘤。第二十一页，本课件共有47页n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 o
18、utcome 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
19、prognostic factors of the primary tumor.factors of the primary tumor.第二十二页，本课件共有47页Figure 1.DevelopmentoflymphaticvesselsinembryogenesisandcancerSomeoftheproteinsthatareimportantintheseeventsareshownunderneatheachsection.Arrowsdenotethedirectionoflymphflowinthelymphaticvessels.第二十三页，本课件共有47页n转移转移met
20、astasismetastasisn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血道转移血道转移第二十四页，本课件共有47页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。第二十五页，本课件共有47页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
21、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第二十六页，本课件共有47页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，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n十六种十六种a a亚单位和亚单位和8 8种种b b亚单位亚单
22、位第二十七页，本课件共有47页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 P第二十八页，本课件共有47页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第二十九页，本课件共有47页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
23、 cells adhere to by a process similar to that of LC homing.In this model,cells in flow are captured on the endothelial surface.第三十页，本课件共有47页transientadhesiveinteractionsbycellswithendothelialselectins(rolling),andfirmlyanchoredon(firmadhesion)toenableentryintotheunderlyingtissue.Theselectins,particu
24、larlyE-selectin,arerecognizedtomediateadhesionandthuspotentiateofcertaincancersn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 family第三十一页，本课件共有47页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nCD44nAtransmembraneprotein nEssentialforthehomingandpropertiesofleukemicCells,nCD44hasalsobeenfoun
25、dtosupportanchorage-independentgrowthinvitroandtumorgrowthandinexperimentalmodelsofsolidcancers 第三十二页，本课件共有47页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第三十三页，本课件共有47页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
26、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第三十四页，本课件共有47页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第三十五页，本课件共有47页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n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变为肿瘤血管变为肿瘤血管nVEGFVEGF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第三十六页，本课件共有47页Fig.1
27、Switchingontheangiogenicphenotypeintumorsbygeneticandepigeneticfactors.Bothmalignantandnonmalignantcellsproducemultipleangiogenicfactorsandcytokinestoinducetumorneovascularization.Endogenousangiogenesisinhibitorsaredownregulatedtosupporttheangiogenicphenotype第三十七页，本课件共有47页n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
28、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Fig.1.SchematicdiagramshowinghowproductionofVEGF-CandVEGF-Cintumorscaninducelymphangiogenesis,leadingtoincreasedlymphaticvesseldensityinthevicinityofthetumor,andsubsequentlytometastasisofinvasivetumorcellsviathelymphvessels.Fig.1.第三十八页，本课件共有47页n转移灶的形成和生长转移灶的形成和
29、生长第三十九页，本课件共有47页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)catalyzetheexchangeof-phosphatebetweennucleoside(and2-deoxynucleoside)triphosphatesanddiphosphateswithformationofahigh-energyphosphohistidineintermediate(ParksandAgarwal1973).Theyareenc
30、odedbytheNMEgenes(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n高度表达高度表达nm23nm23表现为低转移属性表现为低转移属性第四十页，本课件共有47页n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mtal第四十一页，本课件共有47页n肿瘤侵袭和转移相关基因肿瘤侵袭和转移相关基因nTiam1 基因基因鼠鼠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。产物具有产物具有1591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TIAM1 T-cell lymphoma
31、 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,Bc
32、randT-lymphomainvasionandmetastasis1(Tiam1),havebeenidentifiedasoncogenes.第四十二页，本课件共有47页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 expr
33、ession correlates with the invasion and metastasis 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 基因基因鼠鼠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。第四十三页，本课件共有47页Overexpression of Tiam1 in hepatocellular carcinomas predicts poor prognosis of HCC patientsYi Ding1,Bin Chen2,Shuang Wang3,Liang Zhao3,
34、Juanzhi Chen3,Yanqing Ding3,Longhua Chen1*and Rongcheng Luo2*Int.J.Cancer:124,653658(2009)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 基因基因 鼠鼠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。第四十四页，本课件共有47页生长因子通过生长因子通过Ras信号通路，信号通路，导致细胞增殖。导致细胞增殖。转染给转染给NIH3T3细胞，细胞，引起大量侵袭和转移。引起大量侵袭和转移。Activated KrasG12D is associated
35、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 n肿瘤侵袭和转移相关基因肿瘤侵袭和转移相关基因nRas 基因基因包括包括H-ras，K-ras 和和N-ras 三类，三类，第四十五页，
36、本课件共有47页Results:TheKrasG12Dknockdowncellsexhibitedasignificantdecreaseinmotility(P0.0001),invasion(P0.0001),anchorage-dependent(P0.0001)andanchorage-independentgrowth(P0.0001),proliferation(P0.005)andanincreaseincelldoublingtime(P0.005)invitroandadecreaseintheincidenceofmetastasesuponorthotopicimpla
37、ntationintonudemice.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
38、 several proteins involved in cell survival,invasion and metastasis was decreased in the KrasG12Dknockdowncells.Conclusions:TheresultsofthisstudysuggestthattheKrasG12DallelepromotesmetastasisinPCcellspartlythroughthedownregulationofE-cadherin.n肿瘤侵袭和转移相关基因肿瘤侵袭和转移相关基因nRas 基因基因包括包括H-ras，K-ras 和和N-ras 三类，三类，British Journal of Cancer 104,1038-1048(15 March 2011)第四十六页，本课件共有47页感感谢谢大大家家观观看看第四十七页，本课件共有47页