《肿瘤分子生物学[3]细胞永生化与肿瘤发生教材》由会员分享，可在线阅读，更多相关《肿瘤分子生物学[3]细胞永生化与肿瘤发生教材（34页珍藏版）》请在金锄头文库上搜索。
1、细胞永生化与肿瘤发生,Xian Jiaotong University,2016.2.,Page 2,肿瘤概念,Cancer is a genetic disease, arising from an accumulation of mutations that promote clonal selection of cells with increasingly aggressive behavior. The vast majority of mutations in cancer are somatic and are found only in an individuals cance
2、r cells. However, about 1% of all cancers arise in individuals with an unmistakable hereditary cancer syndrome. These individuals carry a particular germline mutation in every cell of their body. Science Vol. 278. no. 5340, pp. 1043 1050, 7 November 1997,肿瘤是机体在各种致瘤因素的作用下，局部组织的细胞在基因水平上失去对其生长的正常调控，导致克
3、隆性异常增生而形成的新生物（病理学卫生部统编教材第五版2001） 。,Page 3,癌细胞的基本特征 1、细胞生长与增殖失去控制 2、具有浸润性和扩散性 3、细胞间相互作用改变 4、蛋白表达谱系或蛋白活性改变 5、mRNA转录谱系改变 6、体外培养的恶性转化细胞的特征 二、癌基因与抑癌基因 癌基因控制细胞生长和分裂的正常基因的一种突变形式 抑癌基因正常细胞增殖过程中的负调控因子 三、肿瘤的发生是基因突变逐渐积累的结果,Page 4,Normal cell populations register the number of cell generations,C. elegance- The l
4、ineage of all 959 somatic cells in the adult body( could be) has been traced to their founder and can be depicted as a pedigree,Page 5,发育生物学：关注的是不同细胞谱系中的细胞个体如何从其周围获取信息，使其进入特定的分化程序， 而不关注与肿瘤发生最相关的问题， 有无特定的 控制系统 决定一个生物体特定的细胞谱系一生中能够传多少代？一个细胞系谱的分支 是否能够无限制生长（grow),或者每一个细胞谱系分裂次数是否为预先设定，有限的？,Page 6,1960 Leo
5、nard Hayfliks work by counting the number of times that population of cells had doubled . When the cells enter into senescence , they could remain viable but nonproliferating for as long as a year,Page 7,Loss of proliferative capacity with age,Page 8,Senescent cells- When the cells enter into senesc
6、ence, they cease proliferating but remain viable, “Fried egg appearance” is the morphological feature because of the enlarged cytoplasm. Metabolically, senescent cells characteristically express the senescence-associated, acidic -galactosidase enzyme, which can be detected by supplying them with sub
7、strate that turns blue upon cleavage by this enzyme,Page 9,Cancer cells need to become immortal in order to form cancer,Generations of cells forming a tumor(a) 1cm3=109 cell, life-threatening tumor 103cm3 1012 cell, 103 210 , hence 1012 240 cycles Cell PD 60 1018cell 109cm3 106kg,Page 10,Generations
8、 of cells forming a tumor(b) Cell populations that are evolving toward the neoplasitic state and those that are already neoplastic experience substantial attrition during each cell generation,How can normal cells throughout the body possibly remember their replicative history ? how can cancer cells
9、erase the memory of this history and acquire the ability to proliferate indefinitely?,Page 11,Cell physiologic stresses impose a limitation on replication,Influence of culture conditions on the onset of senescence Oxygen concentration Plastic or feeder cell in the culture influence the expression of
10、 tumor suppressor gene expression, so to the senescence In vitro mechanism - senescence -,Page 12,Increased expression of p16 and p21 progressively during extended culture in vitro,Ectopic expression of p16 in cells caused them to develop many of the attributes of replicative senescence,Normal cells
11、,Forced expression of P16,Senescent cells,Actin stress fibers (orange) Focal contacts with the substrate (yellow),Page 13,Role of large T antigen in circumventing senescence Inactivation of both pRB and p53 is needed to ensure that these cells do not senesce in culture. This can be archived through
12、the expression of the SV40 large T antigen in the target cells,Page 14,Evidence of senescent cells in living tissues A definitive proof that senescence is an in vivo phenomenon is critical to our understanding of cancer development.,Brca1 mutant which is involved in maintaining genomic integrity,The
13、 presence of senescent human melanocyts within dysplastic nevi,Treatment of tumors with chemotherapeutic drugs carboplatin and taxol prior to surgical excision of the tumor,Page 15,Senescence represents a halt in cell proliferation with retention of cell viability over extended periods of time, whil
14、e Crisis involves death by apoptosis . Senescent cells seem to have a reasonably(but not totally) stable karyotype, while cells in crisis show widespread karyotypic instability,危象的时相、形态变化提示其触发机制是独立于衰老的， 启动危象的分子装置确实是 细胞谱系从胚胎早期（进入 growth-and-division cycle)以后记录细胞连续传代的功能性计数装置,The proliferation of cultu
15、red cells is limited by the telomeres of their chromosomes,Page 16,Barbara McClintock 1941 年报道了玉米染色人体端粒和转座子，获得1983年诺奖,Telomeres detected by FISH(left),( right)karyotype seen in left compared with that of cells have been deprived of TRF2 实验室DNA 转染技术显现出哺乳动物染色体线状结构的致命缺陷。 真核细胞转染DNA 需要线状 化-使其不稳定 TA-质粒,Pa
16、ge 17,Shortening of telomeric DNA (5-TTAGGG-3 tandemly repeated hexanucleotide sequence) in concert with cell proliferation,Page 18,Dicentric chromosomes, anaphase bridges, and internuclear bridges,Page 19,Mechanisms of breakage- fusion-bridge cycles,Page 20,端粒与细胞危象 进入危象的细胞准确的呈现染色体缺失端粒时的核型紊乱模式 。 这些细胞内融合的染色体（breakage- fusion-bridge）端粒很短， 甚至端粒全无。 提示触发细胞危象分子机制 存在于端粒内。,Page 21,测量端粒DNA的长度不能准确预测细胞的增殖潜能 即便已知一个细胞端粒DNA的长度，该细胞距离危象的增殖代数并不能精确预测。一个细胞内的端粒缩短速率不同， 细胞内最短的端粒可能决定细胞的增殖潜能， 因为
