肿瘤分子生物学3细胞永生化与肿瘤发生.ppt

1、XIAN JIAOTONG UNIVERSITYPage 1肿瘤概念肿瘤概念 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 cancer cells. However,

2、 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， 导致克隆性异常增生而形成的新生物 （

3、 病理学卫生部统编教材第五版 2001） 。XIAN JIAOTONG UNIVERSITYPage 2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XIAN JIAOTONG UNIVERSITYPage 3Normal cell populations register the number of cell genera

4、tionsC. elegance-The lineage of all 959 somatic cells in the adult body( could be) has been traced to their founder and can be depicted as a pedigreeXIAN JIAOTONG UNIVERSITYPage 4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（ gr

5、ow),或者每一个细胞谱系分裂次数是否为预先设定，有限的？ XIAN JIAOTONG UNIVERSITYPage 51960 Leonard 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 yearXIAN JIAOTONG UNIVERSITYPage 6Loss o

6、f proliferative capacity with ageXIAN JIAOTONG UNIVERSITYPage 7Senescent cells-When the cells enter into senescence, they cease proliferating but remain viable, “Fried egg appearance” is the morphological feature because of the enlarged cytoplasm. Metabolically, senescent cells characteristically ex

7、press the senescence-associated, acidic -galactosidase enzyme, which can be detected by supplying them with substrate that turns blue upon cleavage by this enzyme XIAN JIAOTONG UNIVERSITYPage 8Cancer cells need to become immortal in order to form cancerGenerations of cells forming a tumor(a)1cm3=109

8、 cell, life-threatening tumor 103cm3 1012 cell,103 210 , hence 1012 240 cyclesCell PD 60 1018cell 109cm3 106kgXIAN JIAOTONG UNIVERSITYPage 9Generations of cells forming a tumor(b) Cell populations that are evolving toward the neoplasitic state and those that are already neoplastic experience substan

9、tial attrition during each cell generationHow can normal cells throughout the body possibly remember their replicative history ? how can cancer cells erase the memory of this history and acquire the ability to proliferate indefinitely?XIAN JIAOTONG UNIVERSITYPage 10Cell physiologic stresses impose a limitation on replicationInfluence of culture conditions on the onset of senescenceOxygen concentrationPlastic or feeder cell in the culture influence the expression of tumor suppressor gene expression, so to the senescenceIn vitro mechanism - senescence -