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1、肿瘤的生物化学特性u物质代谢及酶的变化物质代谢及酶的变化u肿瘤细胞的分化肿瘤细胞的分化u肿瘤细胞的生长肿瘤细胞的生长u肿瘤细胞扩散的过程机制肿瘤细胞扩散的过程机制u肿瘤侵袭和转移相关基因肿瘤侵袭和转移相关基因核酸代谢核酸代谢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DNADNA拓扑异构酶拓扑异构酶u物质代谢及酶的变化物质代谢及酶的变化端粒酶端粒酶DNADNA拓扑异构酶拓扑异构酶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。 DNADNA拓扑异构酶通过形
2、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 核酸代谢核酸代谢u物质代谢及酶的变化物质代谢及酶的变化(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.
3、(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
4、 mitotic counting mechanism in vitro 核酸代谢核酸代谢u物质代谢及酶的变化物质代谢及酶的变化端粒酶端粒酶Each mammalian chromosome end has a distinctive DNA-protein structure, which prevents the degradation and fusion of chromosome ends by helping distinguish chromosome ends from a double strand break in the genomic DNA.Mammalianhave
5、astretchofasimplerepeatsequenceunit(TTAGGG)andin,lengthis1520kb.Fiftyto200bpofthetelomericDNAshortensateachroundofmitosis.WhenaverageDNAreachesacriticallyshortlength,about47kb,isarrestedIrreversibly.核酸代谢核酸代谢端粒酶端粒酶u物质代谢及酶的变化物质代谢及酶的变化u物质代谢及酶的变化物质代谢及酶的变化核酸代谢核酸代谢蛋白质代谢蛋白质代谢糖代谢糖代谢酶系统酶系统u物质代谢及酶的变化物质代谢及酶的变化
6、酶系统酶系统增殖相关和分化相关的酶增殖相关和分化相关的酶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u肿瘤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)同一来源的同一来源的幼稚细胞幼稚细胞?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态结构特定的形态结构稳定性稳定性全能性全能性选择性选择性条件可逆
7、性条件可逆性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。肿瘤细胞分化异常的机制肿瘤细胞分化异常的机制遗传学改变遗传学改变信号转化异常信号转化异常微环境的影响微环境的影响诱导分化治疗肿瘤诱导分化治疗肿瘤u肿瘤细胞的生长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
8、 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肿瘤细胞的生长肿瘤细胞的生长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 ant
9、igens 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,theprognostic
10、andpredictiveroleoftheproliferativemarkershadtobeassessedthroughmultivariateanalyses.Onehundredandthirty-twopapersfulfilledthesecriteriaand159516patientsanalyzed.u肿瘤细胞的生长肿瘤细胞的生长免疫组织化学方法免疫组织化学方法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 cy
11、cle, 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,h
12、avealsobeendiscovered;whichstimulatecellstoprogressthroughthecellcyclemuchmoreefficientlythanthefulllengthcyclinE1Cyclin E was prognostic in seven out of 10 studies.u肿瘤细胞的生长肿瘤细胞的生长免疫组织化学方法免疫组织化学方法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 (LM
13、W) 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肿瘤细胞的生长肿瘤细胞的生长细胞周期蛋白细胞周期蛋白D-type cyclins are other key regulat
14、or 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 ce
15、ll is committed to divideA 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
16、瘤细胞的生长肿瘤细胞的生长细胞周期蛋白细胞周期蛋白u肿瘤的生长与扩散肿瘤的生长与扩散l肿瘤的扩散方式肿瘤的扩散方式直接蔓延直接蔓延转移转移metastasismetastasis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，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。转移转移metastasismetastasisu肿瘤的生长与扩散肿瘤的生长与扩散肿瘤的扩散方式肿瘤的扩散方式淋巴道转移淋巴道转移Lymphatic metastasis is a predictor of poor Lymphatic metastasis
17、 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 pa
18、tients independent of other prognostic factors of the primary tumor.factors of the primary tumor.Figure 1. DevelopmentoflymphaticvesselsinembryogenesisandcancerSomeoftheproteinsthatareimportantintheseeventsareshownunderneatheachsection.Arrowsdenotethedirectionoflymphflowinthelymphaticvessels.转移转移met
19、astasismetastasisu肿瘤的生长与扩散肿瘤的生长与扩散肿瘤的扩散方式肿瘤的扩散方式血道转移血道转移转移转移metastasismetastasisu肿瘤的生长与扩散肿瘤的生长与扩散l肿瘤的扩散方式肿瘤的扩散方式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。u肿瘤细胞扩散的过程机制肿瘤细胞扩散的过程机制肿瘤侵袭是转移的前提；肿瘤侵袭是转移的前提；侵袭和转移的步骤：侵袭和转移的步骤：脱离原发瘤群体脱离原发瘤群体向周围组织浸润向周围组织浸润与局
20、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穿透管壁，穿透管壁， 在基质中增生在基质中增生转移灶的形成和生长转移灶的形成和生长u肿瘤细胞扩散的过程机制肿瘤细胞扩散的过程机制l细胞黏附与细胞黏附分子细胞黏附与细胞黏附分子侵袭和转移的步骤：侵袭和转移的步骤：脱离原发瘤群体脱离原发瘤群体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integrin跨膜糖蛋白跨膜糖蛋白十六种十六种a a亚单位和亚单位和8 8种种b b亚单位亚单位u肿瘤细胞扩散的过程机制肿瘤细胞扩散的过程机制l细胞黏附与细胞黏附分子细胞黏附与细胞黏附分子cadherin
21、与细胞骨架连接与细胞骨架连接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 Pu肿瘤细胞扩散的过程机制肿瘤细胞扩散的过程机制l细胞黏附与细胞黏附分子细胞黏附与细胞黏附分子IgSF跨膜蛋白跨膜蛋白具有与具有与IgIg类似的结构类似的结构u肿瘤细胞扩散的过程机制肿瘤细胞扩散的过程机制l细胞黏附与细胞黏附分子细胞黏附与细胞黏附分子Selectin familycancer cells adhere to by a process similar to that of LC homing. In this model, cells in flow are captured
22、on the endothelial surface.transientadhesiveinteractionsbycellswithendothelialselectins(rolling),andfirmlyanchoredon(firmadhesion)toenableentryintotheunderlyingtissue.Theselectins,particularlyE-selectin,arerecognizedtomediateadhesionandthuspotentiateofcertaincancersu肿瘤细胞扩散的过程机制肿瘤细胞扩散的过程机制l细胞黏附与细胞黏附分
23、子细胞黏附与细胞黏附分子Selectin familyu肿瘤细胞扩散的过程机制肿瘤细胞扩散的过程机制l细胞黏附与细胞黏附分子细胞黏附与细胞黏附分子CD44Atransmembraneprotein EssentialforthehomingandpropertiesofleukemicCells, CD44hasalsobeenfoundtosupportanchorage-independentgrowthinvitroandtumorgrowthandinexperimentalmodelsofsolidcancers u肿瘤细胞扩散的过程机制肿瘤细胞扩散的过程机制肿瘤细胞从原发灶分离的机
24、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。肿瘤细胞表面黏附分子减少。癌细胞钙含量降低癌细胞钙含量降低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肿瘤细胞表面电荷增加肿瘤细胞表面电荷增加l肿瘤细胞向周围组织的浸润肿瘤细胞向周围组织的浸润细胞外基质的降解细胞外基质的降解瘤细胞的运动瘤细胞的运动趋化因子的作用趋化因子的作用肿瘤血管生成肿瘤血管生成肿瘤血管生成肿瘤血管生成l肿瘤细胞向周围组织的浸润肿瘤细胞向周围组织的浸润肿瘤血管生成肿瘤血管生成肿瘤组织中微血管的来源肿瘤组织中微血管的来源瘤细胞生成的多种生长因子瘤细胞生成的多种生长因子诱导瘤体生成微血管诱导瘤体生成微血管残存
25、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VEGFVEGF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Fig.1Switchingontheangiogenicphenotypeintumorsbygeneticandepigeneticfactors.Bothmalignantandnonmalignantcellsproducemultipleangiogenicfactorsandcytokinestoinducetumorneovascularization.Endogenousangiogenesisinhibitorsaredo
26、wnregulatedtosupporttheangiogenicphenotype肿瘤细胞侵入血管和淋巴管肿瘤细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,andsubsequentlytometastasisofinvasiv
27、etumorcellsviathelymphvessels.Fig.1.l转移灶的形成和生长转移灶的形成和生长u肿瘤侵袭和转移相关基因肿瘤侵袭和转移相关基因Nm23Nm23基因基因NM23-H1 and NM23-H2 in humanNucleosidediphosphatekinases(NDPKs)catalyzetheexchangeof-phosphatebetweennucleoside(and2-deoxynucleoside)triphosphatesanddiphosphateswithformationofahigh-energyphosphohistidineinterm
28、ediate(ParksandAgarwal1973).TheyareencodedbytheNMEgenes(alsoknownasNM23).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u肿瘤侵袭和转移相关基因肿瘤侵袭和转移相关基因肿瘤转移相关基因肿瘤转移相关基因mtalu肿瘤侵袭和转移相关基因肿瘤侵袭和转移相关基因Tiam1 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
29、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
30、,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 expre
31、ssion correlates with the invasion and metastasis of nasopharyngeal carcinoma cells.u肿瘤侵袭和转移相关基因肿瘤侵袭和转移相关基因Tiam1 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。Overexpression of Tiam1 in hepatocellular carcinomas predicts poor prognosis of HCC patientsYi Ding1, Bin Chen2, Shuang Wang3, Liang Zhao3, Juanzhi Chen
32、3, Yanqing Ding3, Longhua Chen1* and Rongcheng Luo2*Int. J. Cancer: 124, 653658 (2009)2008 Wiley-Liss, Inc.u肿瘤侵袭和转移相关基因肿瘤侵袭和转移相关基因Tiam1 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。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 with invasion an
33、d 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肿瘤侵袭和转移相关基因肿瘤侵袭和转移相关基因Ras 基因基因包括包括H-ras， K-ras 和和N-ras 三类，三类， Results:TheK
34、rasG12Dknockdowncellsexhibitedasignificantdecreaseinmotility(P0.0001),invasion(P0.0001),anchorage-dependent(P0.0001)andanchorage-independentgrowth(P0.0001),proliferation(P0.005)andanincreaseincelldoublingtime(P0.005)invitroandadecreaseintheincidenceofmetastasesuponorthotopicimplantationintonudemice.
35、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 protei
36、ns involved in cell survival, invasion and metastasis was decreased in the KrasG12Dknockdowncells.Conclusions:TheresultsofthisstudysuggestthattheKrasG12DallelepromotesmetastasisinPCcellspartlythroughthedownregulationofE-cadherin.u肿瘤侵袭和转移相关基因肿瘤侵袭和转移相关基因Ras 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) The EndThe End！
