肿瘤分子生物学[3]细胞永生化与肿瘤发生..pptVIP

Page * Telomere and bone marrow collapse of dyskeratosis congenita X-linked form of the disease, a protein known as dyskerin is absent or malfunctioning. Dyskerin associates with the telomerase-associated RNA subunit (hTR) and helps hTR to assemble in the telomerase holoenzyme. An autosomal dominant version of the same disease is caused by the inheritance of a defective hTR-encoding gene. Cells in proliferating tissues of affected individuals exhibit dicentric chromosomes,which are indicative of interchromosomal fusions. Page * ●培养细胞无限增殖的障碍: 衰老/危象 (senescence and crisis)； 衰老指的是培养细胞处于不增值状态，但仍存活；危象指的是细胞通过凋亡形式而死亡 ●衰老由细胞体外培养条件下的生理性应激（stress)所触发。 虽然在体细胞也存在这一现象，但这一过程在体内限制细胞增殖的作用仍不得其要领 ●危象是由端粒消蚀所致，导致广泛的染色体端-端融合，核型混乱 ，细胞死亡。 Page * ●大多数癌前细胞通过活化表达hTERT逃逸危象 ，有些癌细胞通过ALT 机制再生端粒DNA逃逸危象 ●通过端粒酶的作用或ALT机制稳定其端粒的细胞能够无限增殖，即已获永生化。细胞永生化似乎是所有人类肿瘤发生的关键一步 ●伴随危象的染色体端-端融合导致反复性断裂-融合-桥接循环（breakage-fusion-bridge cycle), 与多种人类实体肿瘤细胞形成的非整倍体核型有关。 Page * * XI’AN JIAOTONG UNIVERSITY 细胞永生化与肿瘤发生 Xi’an Jiaotong University 2016.2. Page * 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, 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（病理学－卫生部统编教材第五版2001） 。 Page * 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 * 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 bee