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1、第十六章肿瘤的诱导分化和凋亡疗法,受精卵的全能性,人体细胞总数：1014 类型：200多种,细胞可以通过增殖来增加数目，那么细胞通过什么方法来改变其结构和功能呢？,细胞分化（Differentiation),由同源细胞逐渐变为在形态结构、生理功能和生化特征等方面具有稳定差异的另一类型细胞的过程。,干细胞,干细胞(stem cells, SC)是一类具有自我复制能力(self-renewing)的多潜能细胞，在一定条件下，它可以分化成多种功能细胞。干细胞是一种未充分分化，尚不成熟的细胞，具有再生各种组织器官和人体的潜在功能，医学界称为“万用细胞,分化异常与肿瘤干细胞,传统观念认为,肿瘤是由体细胞
2、突变而成,每个肿瘤细胞都可以无限制地生长。但这无法解释肿瘤细胞似乎具有无限的生命力以及并非所有肿瘤细胞都能无限制生长的现象 肿瘤干细胞：肿瘤中具有自我更新能力并能产生异质性肿瘤细胞的细胞。,Self renewal and differentiation are random.All cells have equal but low probability ofextensive proliferation. Only cells with selfrenewal capacity can sustain tumor growth.,Distinct classes of cells exis
3、t within atumor. Only a small definable subset, the cancer stem cells can initiate tumorgrowth.,Two General Models for Cancer Heterogeneity异质性,1. All cancer cells are potential cancer stem cells but have a low probability of proliferation in clonogenic assays （随机模式）2. Only a small definable subset o
4、f cancer cells are cancer stem cells that have the ability to proliferate indefinitely.（干细胞模式）,Origin of the Theory of Cancer Stem Cells,Only a small subset of cancer cells is capable of extensive proliferation Liquid TumorsIn vitro colony forming assays:- 1 in 10,000 to 1 in 100 mouse myeloma cells
5、 obtained from ascites away from normal hematopoietic cells were able to form coloniesIn vivo transplantation assays:- Only 1-4% of transplanted leukaemic cells could form spleen coloniesSolid Tumors- A large number of cells are required to grow tumors in xenograft models- 1 in 1,000 to 1 in 5,000 l
6、ung cancer, neuroblastoma cells, ovarian cancer cells, or breast cancer cells can form colonies in soft agar or in vivo,Therapeutic implications of Cancer Stem Cells,Most therapies fail to consider the difference in drug sensitivities of cancer stem cells compared to their non-tumorigenic progeny. M
7、ost therapies target rapidly proliferating non-tumorigenic cells and spare the relatively quiescent cancer stem cells.,第一节 诱导分化与肿瘤治疗,肿瘤细胞在一定条件和诱导分化剂的作用下可以向正常细胞转化,Wnt, Shh, and Notch pathways have been shown to contribute to the self-renewal of stem cells and/or progenitors in a variety of organs, in
8、cluding the haematopoietic and nervous systems. When dysregulated, these pathways can contribute to oncogenesis. Mutations of these pathways have been associated with a number of human tumours, including colon carcinoma and epidermal tumours (Wnt), medulloblastoma and basal cell carcinoma (Shh), and
9、 T-cell leukaemias (Notch).,Pathways involved in self-renewal that are deregulated in cancer cells,诱导分化剂,1. 极性化合物: 包括二甲亚砜(DMSO) 2. 佛波酯(12-O-tetradecanoyl-phorbol-13 acetate，TPA)。3. 维生素D3及其衍生物4. cAMP及其衍生物5. 细胞因子: 包括G-CSF、GM-CSF、IFN、 TGF-、TNF、6. 芳香族脂肪酸: 包括桂皮酸、苯丁酸、苯乙酸及其衍生物等。7. 抗肿瘤药物: 包括MTX、DDP、Ara-c、三尖
10、杉酯碱、抗肿瘤抗生素、地塞米松等。8. 中药提取物及复合制剂: 包括姜黄素、人参总皂甙。9. 维A类化合物:10. 其它类: 包括5-氮杂-2-脱氧胞核苷(ADC)、蛋白磷酸化剂(银毛酸)、星形孢菌素、乳香酸、三氧化二砷等。,全反式维甲酸All-trans-retinoic acid,全反式维甲酸(ATRA)，也叫做维A酸。其抗肿瘤作用的证实被誉为九十年代国际抗癌药物的三大发现之一，具有很强的诱导分化肿瘤细胞作用，备受国际国内医药界的关注，是目前国内治疗急性早幼粒细胞白血病、骨髓异常增生（白血病前期）尤其是早幼粒细胞白血病的临床首选药物。,ATRA联合三氧化二砷治疗APL,位于15号染色体上的
11、早幼粒白血病基因与17号染色体上的维甲酸受体基因易位，形成特定的融合基因，导致急性早幼粒细胞白血病,This schematic presentation of the translocation (15;17)(q22;q12), characteristic of APL (M3), involves the genes PML-RAR-alpha,维甲酸和砷剂通过不同的途径，靶向作用于该型白血病的同一关键致病基因编码的蛋白质。因此提出两药共用的协同靶向治疗设想,思考题,细胞分化、肿瘤细胞分化特点干细胞、肿瘤干细胞诱导分化剂,第三节 诱导凋亡与肿瘤治疗,1972年Kerr Apoptosi
12、s(凋亡) 编程性细胞死亡(programmed cell death，PCD)细胞凋亡是形态学概念，编程性细胞死亡大多表现为细胞凋亡，但并非所有编程死亡的细胞都有细胞凋亡的形态特征,Normal white blood cell Apoptotic white blood cell,During apoptosis (programmed cell death) cells bleb and eventually break apart without releasing contents.,Apoptosis during the metamorphosis of a tadpole in
13、to a frog.The cells in the tadpole tail are induced to undergo apoptosis stimulated by the increases in thyroid hormone that occurs during metamorphosis,C. elegans是研究PCD的理想材料（生命周期短，细胞数量少）。1030 cells generated but 131 cells die,Types of cells that undergo apoptosis,Apoptosis in the embryonic mouse pa
14、w.Apoptosis occurs between 12.5 to 14.5 days in embryogenesis,Apoptosis and normal morphogenesis.TUNEL assay (immunodetection) detects breaks in DNA as cells undergo apoptosis,+ 1 day,Apoptosis is also important in the development of the nervous system,2002年10月7日英国人Sydney 、美国人Horvitz和英国人Sulston ，因在P
15、CD方面的研究获诺贝尔诺贝尔生理与医学奖。,H. Robert Horvitz,John E. Sulston,Sydney Brenner,细胞凋亡与细胞坏死的区别特征 细胞凋亡 细胞坏死诱导因素 生理及弱刺激 强烈刺激膜完整性 保持到晚期 早期即丧失细胞体积 减少、固缩 增大肿胀染色质 凝聚成半月形 稀疏成网状细胞器 无明显变化 肿张破坏溶酶体 保持完整 破坏外溢细胞形状 形成凋亡小体 破裂成碎片基因组DNA 有控降解 随机降解大分子合成 一般需要 不需要基因调控 有 无受累范围 单个细胞丢失 成群细胞死亡后果 不引起炎症反应 引起炎症反应意义 生理死亡方式 病理死亡方式,诱因,形态,分子水平,转归,www.roche-applied-
