肿瘤的生物学特课件

1、 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

2、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 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 e

3、nzymes. (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 u

4、sed as a 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. M

5、ammalian 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, is arrested Irreversibly. 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

6、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 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

7、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：

8、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 death for patients with primary BC, Flow cytometry Flow cytometry 法法 u肿瘤细胞的生长肿瘤细

9、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 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 Engli

10、sh in peer reviewed journals before June 2004 that include at least 100 evaluable patients were selected. In addition, 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

11、516 patients analyzed. 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 cycle, have a temporally distinct and highly regulated pattern of expression, i.e. they are synthesized and degraded at specific stages of

12、 the cell cycle. Cyclin E is the limiting factor for 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 l

13、ength cyclin E1 Cyclin 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 (LMW) isoforms, and both were a reliable prognostic marker in stage IIII BC patients. High levels

14、 of cyclin E1 were predictive of resistance to tamoxifen adjuvant therapy in 108 node-positive BC patients, independently of ER status. Cyclin D1 u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 regulator proteins of the G1 phase progression. The protein is synthesized in response to growth

15、 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 A strong correlation between overexpression of cyclin D1 and

16、HR-positivity has been reported in the majority of trials, but cyclin D1 does not appear to be a strong prognostic marker. In fact, its overexpression has been associated with better RFS in only one study Cyclin D1 u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 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metastasi

17、smetastasis 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metastasismetastasis u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 is a predictor of poor outcome in many solid malignancies .outcome in

18、 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 prognostic factors of the primary tumor.fa

19、ctors of the primary tumor. Figure 1. Development of lymphatic vessels in embryogenesis and cancer Some of the proteins that are important in these events are shown underneath each section. Arrows denote the direction of lymph flow in the lymphatic vessels. 转移转移 metastasismetastasis u肿瘤的生长与扩散肿瘤的生长与扩

20、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metastasismetastasis 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 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 与局部血管或淋巴管密切接触，与局部血管或淋

21、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 与细胞骨

22、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 P 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 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 family cancer cells adhere to by a process similar to that of LC homing. In this model, cells in flow are ca

23、ptured 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 mediate adhesion and thus potentiate of certai

24、n cancers 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 family 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 CD44 A transmembrane protein Essential for the homing and properties of leukemic Cells, CD44 has also been found to support anchorage- independent growth in vitro and tumor growt

25、h and in experimental models of solid cancers 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

26、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. 1 Switching on the angiogenic phenotype in tumors by genetic and epigenetic factors. Both malignant and nonmalignan

27、t 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. Schematic diagram showing how production o

28、f 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. 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 i

29、n 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 NM23)

30、. 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 mtal 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。 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 invasion and metastasis 1 Homo sapiens Zhonghua Bing L

31、i Xue Za Zhi. 2009 Apr;38(4):268-72. Overexpression of Tiam1 gene and its relationship with invasive and metastatic ability of nasopharyngeal carcinoma. Article in Chinese Zhang XM, Ding Y, Chen JZ, Jin H, Yu LN, Li YF, Ding YQ. Currently, many GEFs, including Vav1, LARG, Bcr and T-lymphoma invasion

32、 and metastasis 1 (Tiam1), have been identified as oncogenes. 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 expression correlates wi

33、th 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 patients Yi Ding1, Bin Chen2, Shuang Wang3, Liang Zhao3, Juanzhi Chen3, Yanqing Ding

34、3, 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 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