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单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,单击此处编辑母版标题样式,XIAN JIAOTONG UNIVERSITY,Page,*,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,单击此处编辑母版标题样式,Page,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,*,肿瘤分子生物学细胞永生化与肿瘤发生,肿瘤分子生物学细胞永生化与肿瘤发生,（优选）肿瘤分子生物学细胞永生化与肿瘤发生,（优选）肿瘤分子生物学细胞永生化与肿瘤发生,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,3,癌细胞的基本特征3,Normal cell populations register the number of cell generations,C.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 pedigree,4,Normal cell populations regist,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？,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,1960 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 year,6,1960 Leonard Hayfliks work by,Loss of proliferative capacity with age,7,Loss of proliferative capacity,Senescent 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 express the senescence-associated,acidic,-galactosidase enzyme,which can be detected by supplying them with substrate that turns,blue,upon cleavage by this enzyme,8,Senescent cells-8,Cancer cells need to become immortal in order to form cancer,Generations of cells forming a tumor(a),1cm,3,=10,9,cell,life-threatening tumor 10,3,cm,3,10,12,cell,10,3,2,10,hence 10,12,2,40,cycles,Cell PD 60 10,18,cell 10,9,cm3 10,6,kg,9,Cancer cells need to become,Generations 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 erase the memory of this history and acquire the ability to proliferate indefinitely?,10,Generations of cells forming a,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 tumor suppressor gene expression,so to the senescence,In vitro mechanism-senescence-,11,Cell physiologic stresses impo,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,Forced expression of P16,Senescent cells,Actin stress fibers,(orange),Focal contacts with the,substrate,(yellow),12,Increased expression of p16 a,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 the expression of the SV40 large T antigen in the target cells,13,Role of large T antigen in cir,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 presence of senescent human melanocyts within dysplastic nevi,Treatment of tumors with chemotherapeutic drugs carboplatin and taxol prior to surgical excision of the tumor,14,Evidence of senescent cells in,Senescence,represents a halt in cell proliferation with retention of cell viability over extended periods of time,while,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 cultured cells is limited by the telomeres of their chromosomes,15,Senescence represents a halt i,85%-90%人体肿瘤可检测到明显的端粒酶活性,Telomerase activity and the prognosis of pediatric tumors,Cell physiologic stresses impose a limitation on replication,One of the functions of mismatch repair is to suppress recombination between imperfectly homologous DNA sequences,Inactivation of both pRB and p53 is needed to ensure that these cells do not senesce in culture.,Plastic or feeder cell in the culture influence the expression of tumor suppressor gene expression,so to the senescence,This can be archived through the expression of the SV40 large T antigen in the target cells,One of the functions of mismatch repair is to suppress recombination between imperfectly homologous DNA sequences,Generations of cells forming a tumor(b),Cell PD 60 1018cell 109cm3 106kg,端粒酶
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