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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 f
2、orm 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 th
3、e 50-phosphotyrosine 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 chromosom
4、e ends by helping 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 sh
5、ort length, about 47 kb, is 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
6、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 B
7、C,Flow cytometry 法,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 others.,The Ki-67/MIB 1 protein has a prognostic value for many types of malignant tumors.,Ki-67,Only papers publ
8、ished in English 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 cri
9、teria and 159 516 patients analyzed.,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, have a temporally distinct and highly regulated pattern of expression, i.e. they are synthesized and degraded at specific stages of the cel
10、l 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 length cy
11、clin E1,Cyclin 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 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
12、of resistance to tamoxifen adjuvant therapy in 108 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 to growth factors; its levels reach a maximum in the
13、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 HR-positivity has been reported in the major
14、ity 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,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
15、道转移,Lymphatic metastasis 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.,Figure 1. Development of lymphatic vessels in embryogenesis and
16、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,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
