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1、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)Classification of human DNA topoisomerases.Type IB are the only enzymes that form
2、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-phosphotyros
3、ine covalent bond in the Top2cc.,It is thought that length or integrity of chromosome end is used as a mitotic counting mechanism in vitro,核酸代谢,物质代谢及酶的变化,端粒酶,Each mammalian chromosome end has a distinctive DNA-protein structure,which prevents the degradation and fusion of chromosome ends by helping
4、distinguish chromosome ends from a double strand break in the genomic DNA.,Mammalian have a stretch of a simple repeat sequence unit(TTAGGG)and in,length is 1520 kb.Fifty to 200 bp of the telomeric DNA shortens at each round of mitosis.When average DNA reaches a critically short length,about 47 kb,i
5、s arrested Irreversibly.,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
6、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,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 法,肿瘤细胞的生长,免疫组织化学
7、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-67,Only papers published in English in peer reviewed jo
8、urnals before June 2004 that include at least 100 evaluable patients were selected.Inaddition,the prognostic and predictive role of the proliferative markers had to be assessed through multivariate analyses.One hundred and thirty-two papers fulfilled these criteria and 159 516 patients analyzed.,肿瘤细
9、胞的生长,免疫组织化学方法,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 synthesized and degraded at specific stages of the cell cycle.,Cyclin E is the limiting factor fo
10、r G1 phase progression and S phase entry,Recently,several splice variants of cyclin E1,which are not present in normal cells,have also been discovered;which stimulate cells to progress through the cell cycle much more efficiently than the full length cyclin E1,Cyclin E was prognostic in seven out of
11、 10 studies.,肿瘤细胞的生长,免疫组织化学方法,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.,High levels of cyclin E1 were predictive of resistance to tamoxifen adjuvant therapy in 108
12、 node-positive BC patients,independently of ER status.,Cyclin D1,肿瘤细胞的生长,细胞周期蛋白,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.
13、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 st
14、rong prognosticmarker.In fact,its overexpression has been associated with better RFS in only one study,Cyclin D1,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,Lymphatic metastasis is a predictor of poor outcome in m
15、any solid malignancies.,The presence of lymph node metastases decreases the 5-year survival of melanoma patients independent of other prognostic factors of the primary tumor.,Figure 1.Development of lymphatic vessels in embryogenesis and cancerSome of the proteins that are important in theseevents a
16、re shown underneath each section.Arrows denote the direction of lymph flow in thelymphatic vessels.,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
17、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,Selectin family,cancer cells adhere to by a process similar to that o
18、f LC homing.In this model,cells in flow are captured on the endothelial surface.,transient adhesive interactions by cells with endothelial selectins(rolling),and firmly anchored on(firm adhesion)to enable entry into the underlying tissue.The selectins,particularly E-selectin,are recognized to mediat
19、e adhesion and thus potentiate of certain cancers,肿瘤细胞扩散的过程机制,细胞黏附与细胞黏附分子,Selectin family,肿瘤细胞扩散的过程机制,细胞黏附与细胞黏附分子,CD44,A transmembrane protein,Essential for the homing and properties of leukemicCells,CD44 has also been found to support anchorage-independent growth in vitro and tumor growth and in ex
20、perimental models of solid cancers,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.1 Switching on the angiogenic phenoty
21、pe in tumors by genetic and epigenetic factors.Both malignant and nonmalignant cells produce multiple angiogenic factors and cytokines to induce tumor neovascularization.Endogenous angiogenesis inhibitors are down regulated to support the angiogenic phenotype,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
22、.Schematic diagram showing how production of VEGF-C and VEGF-C in tumors can induce lymphangiogenesis,leading to increased lymphatic vessel density in the vicinity of the tumor,and subsequently to metastasis of invasive tumor cells via the lymph vessels.,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-H1 a
23、nd NM23-H2 in human,Nucleoside diphosphate kinases(NDPKs)catalyze the exchange of-phosphate between nucleoside(and 2-deoxynucleoside)triphosphates and diphosphates with formation of a high-energy phosphohistidine intermediate(Parks and Agarwal 1973).They are encoded by the NME genes(also known as NM
24、23).,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,TIAM1 T-cell lymphoma invasion and metastasis 1 Homo sapiens,Zhonghua Bing Li Xue Za Zhi.2009 Apr;38(4):268-72.Overexpression of Tiam1 gene and its relationship with invasi
25、ve and metastatic ability of nasopharyngeal carcinoma.Article in ChineseZhang XM,Ding Y,Chen JZ,Jin H,Yu LN,Li YF,Ding YQ.,Currently,many GEFs,including Vav1,LARG,Bcr and T-lymphoma invasion and metastasis 1(Tiam1),have been identified as oncogenes.,RESULTS:Tiam1 over expression significantly increa
26、sed 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.,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。,Overexpression
27、 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.,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NIH
28、3T3细胞，引起大量侵袭和转移。,Activated KrasG12D is associated with invasion and metastasis of pancreatic cancer cells through inhibition of E-cadherin,British 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,肿瘤侵袭和转移相关基因,Ras
29、基因,包括H-ras，K-ras 和N-ras 三类，,Results:The KrasG12D knockdown cells exhibited a significant decrease in motility(P0.0001),invasion(P0.0001),anchorage-dependent(P0.0001)and anchorage-independent growth(P0.0001),proliferation(P0.005)and an increase in cell doubling time(P0.005)in vitro and a decrease in
30、the incidence of metastases upon orthotopic implantation into nude mice.The knockdown of the KrasG12D allele led to a significant increase in the expression of E-cadherin(mRNA and protein)both in vitro and in vivo.This was associated with a decrease in the expression of phoshpo-ERK-1/2,NF-B and MMP-
31、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 KrasG12D knockdown cells.Conclusions:The results of this study suggest that the KrasG12D allele promotes metastasis in PC cells partly through the downregulation of E-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，,British Journal of Cancer 104,1038-1048(15 March 2011),The End！,
