肿瘤的生物学特性(高级教育)课件

1、肿瘤的生物化学特性1经验课堂肿瘤的生物化学特性1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过程机制肿瘤侵袭和转移相关基因2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经验课堂3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拓扑异构酶物质代谢及酶的变化端粒酶4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

2、5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 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

3、. The arrow indicates the reversible (religation) reaction, which is favored under normal conditions. G) Scheme of the 50-phosphotyrosine covalent bond in the Top2cc. 6经验课堂(A) Classification of human DN7经验课堂7经验课堂It is thought that length or integrity of chromosome end is used as a mitotic counting m

4、echanism 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 distinguish chromosome ends from a double strand break in the genomic DNA.8经验课堂It is thought that length or Mammalian have

5、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, is arrested Irreversibly.核酸代谢端粒酶物质代谢及酶的变化9经验课堂Mammalian have a stretch of a物质代谢及酶的变

6、化核酸代谢蛋白质代谢糖代谢酶系统10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11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?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12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

7、瘤是由于起源组织中的干细胞丧失了分化的能力。13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1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分化治疗肿瘤14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

8、values and increased risk of recurrence and death for patients with primary BC,Flow cytometry 法15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：肿瘤细胞的生长免疫组织化学方法Several monoclonal antibodies reacting with different proliferating cell nuclear antigens have been described, such as PCNA, Ki-67 and MIB 1, KiS1 and oth

9、ers.The Ki-67/MIB 1 protein has a prognostic value for many types of malignant tumors.Ki-67Only papers published in English in peer reviewed journals before June 2004 that include at least 100 evaluable patients were selected. Inaddition, the prognostic and predictive role of the proliferative marke

10、rs had to be assessed through multivariate analyses. One hundred and thirty-two papers fulfilled these criteria and 159 516 patients analyzed.16经验课堂肿瘤细胞的生长免疫组织化学方法Several monoclo肿瘤细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, h

11、ave 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, several splice variants of cyclin E1, which are not present in normal

12、cells, have also been discovered; which stimulate cells to progress through the cell cycle much more efficiently than the full length cyclin E117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 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

13、 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.18经验课堂Cyclin E was prognostic

14、 in sevCyclin 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. It appears that the association of cyclin D1 to Cd

15、k is crucial to drive cells to the restriction point where the cell is committed to divide19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 of cyclin D1 and HR-positivity has been reported in the majority of trials, but cyclin D1 does not appear to be a strong prognosti

16、cmarker. In fact, its overexpression has been associated with better RFS in only one studyCyclin D1肿瘤细胞的生长细胞周期蛋白20经验课堂A strong correlation between o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。21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metastasi转移metastasis肿瘤的生长与扩散肿瘤的扩散方式淋巴道转移Lymphatic m

17、etastasis is a predictor of poor outcome in many 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.22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. Development of lymphatic vessels i

18、n embryogenesis and cancerSome of the proteins that are important in theseevents are shown underneath each section.Arrows denote the direction of lymph flow in thelymphatic vessels.23经验课堂Figure 1. Development of lymp转移metastasis肿瘤的生长与扩散肿瘤的扩散方式血道转移24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转移metastasis肿瘤的生长

19、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。25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， 在基质中增生转移灶的形成和生长26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

20、单位27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； P28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cadherin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29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跨膜蛋白肿瘤细胞扩散的过程机制细胞黏附与细胞黏附分子Selectin familycancer cells adhere to by a process similar to that of L

21、C homing. In this model, cells in flow are captured on the endothelial surface.30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Selectintransient adhesive interactions by cells with endothelial selectins(rolling), and firmly anchored on (firm adhesion) to enable entry into the underlying tissue. The selectins, particula

22、rly E-selectin, are recognized to mediate 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 family31经验课堂transient adhesive interaction肿瘤细胞扩散的过程机制细胞黏附与细胞黏附分子CD44A transmembrane protein Essential for the homing and properties of leukemicCells, CD44 has also been found to su

23、pport anchorage-independent growth in vitro and tumor growth and in experimental models of solid cancers 32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 tr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33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34经验课堂肿瘤细胞向周围组

24、织的浸润细胞外基质的降解瘤细胞的运动趋化因子肿瘤血管生成肿瘤细胞向周围组织的浸润35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36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. 1 Switching on the angiogenic phenotype in tumors by genetic and epigenetic factors. Both malignant and nonmali

25、gnant cells produce multiple angiogenic factors and cytokines to induce tumor neovascularization. Endogenous angiogenesis inhibitors are down regulated to support the angiogenic phenotype37经验课堂Fig. 1 Switching on the angiog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.Schematic diagram showing how producti

26、on 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. 38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转移灶的形成和生长39经验课堂转移灶的形成和生长39经验课堂肿瘤侵袭和转移相

27、关基因Nm23基因NM23-H1 and NM23-H2 in humanNucleoside 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

28、 genes (also known as NM23).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40经验课堂肿瘤侵袭和转移相关基因Nm23基因NM23-H1 and N肿瘤侵袭和转移相关基因肿瘤转移相关基因mtal41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

29、. 2009 Apr;38(4):268-72.Overexpression of Tiam1 gene and its relationship with invasive 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

30、1 (Tiam1), have been identified as oncogenes.42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: 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 expres

31、sion 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。43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 predicts poor prognosis of HCC patientsYi Ding1, Bin Chen2, Shuang Wang3, Liang Zhao3, Juanzh

32、i 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。44经验课堂Overexpression of Tiam1 in hep生长因子通过Ras信号通路， 导致细胞增殖。转染给NIH3T3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-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 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， 45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: Th