肿瘤课件：肿瘤病因与发病机制.ppt

单击此处编辑母版标题样式,编辑母版文本样式,第二级,第三级,第四级,第五级,*,*,肿瘤（四）,肿瘤病因与发病机制,1.,肿瘤标志物,标志物不能作为肿瘤诊断,能够用于肿瘤筛查,肿瘤特异性抗原,(tumor-specific antigen),：不同个体不同肿瘤相关抗原,(tumor-associated antigen),：临床肿瘤的辅助诊断与预后判断AFP,：肝细胞癌、内胚窦瘤,/,卵黄囊瘤,CEA,：胃癌、肠癌,PSA,：前列腺癌，但前列腺炎亦增高,HCG,：葡萄胎、绒毛膜上皮癌、畸胎瘤,CA-125,：卵巢癌，子宫内膜异位症亦增高,CA19-9,：结肠癌、食管癌、肝癌，胰腺炎、肝硬化、胆管阻塞亦增高,CA15-3,：与乳腺癌复发有关,2.,肿瘤分子诊断,（,1,）良恶性诊断,Ig,与,TCR,基因重排检测,确定或排除,T,、,B,细胞淋巴瘤,单克隆阳性对照,多克隆对照,阴性对照,（,2,）预后与生物学行为判断,特定遗传学异常与不良预后有关,指导治疗与判断预后,Her-2/NEU,扩增：乳腺癌，预后差,NMYC,扩增：神经母细胞瘤，预后差，进展快，发生率：,20-25%,检测方法：,IHC,（免疫组化）,FISH,（荧光原位杂交）,PCR,（聚合酶链式反应）,乳腺癌,Her-2,IHC,FISH,双微染色体,均质染色区,神经母细胞瘤,MYCN,FISH,神母,MYCN,扩增原理：,DM,HSR,绿色,MCYN,，红色,2p24.3,（,3,）微小残留病变检测,循环中微量癌细胞（进展）,治疗后残留病变检测,BCR-ABL1,：,CML,，格列卫靶点,FISH,、,PCR,1959,年发现,染色体上检测,BCR-ABL1,细胞核上检测,BCR-ABL1,BCR/ABL1,检测到,ABL1,游离基因,（红）,，无融合基因,（,4,）遗传易感性筛查,肿瘤遗传易感性,等位基因突变,行预防性手术,抑癌基因,BRCA1,肿瘤是多基因病,单基因遗传极少,抑癌基因失活,癌基因激活,（,5,）治疗决策,肿瘤靶向治疗,个体化治疗,有则用，无则弃,蛋白与基因检测,IHC,、,PCR,、,FISH,二代测序,外显子测序,全基因组测序,表达谱测序,基因表达基础,GAPDH,GAPDH,ALK-EML4,不同剪切体,RT-PCR,扩增,肿瘤靶向酪氨酸激酶（,TK,）,酪氨酸特异性蛋白激酶,ATP,酪氨酸残基磷酸化活化,受体,TK,（约,20,个蛋白家族）、胞质,TK,、核内,TK,激活受体的常见配体：,EGF,、,PDGF,、,FGF,、,NGF,、,IGF,、,VEGF,配体,-,受体结合，受体形成二聚体，胞内区酪氨酸残基相互磷酸化,TK,活性,第二信使，转录、生长、发育、凋亡、迁移、侵袭,肿瘤靶向治疗,-,酪氨酸激酶抑制剂（,TKI,）,TK,活性是很多蛋白质功能活化的基础,肿瘤细胞依赖,TK,功能,确定肿瘤细胞生长优势途径,胞膜受体激活,细胞内激活,胞内转录激活,阻断配体,阻断受体,抑制下游靶点,曲妥珠单抗,EGFR,：乳腺癌,伊马替尼,SCF,、,PDGF,、,ABL-TK,：,CML,、,GIST,、,MPN,伊马替尼、达沙替尼（施达赛）、尼罗替尼,阻断,BCR-ABL1,蛋白的融合：,CML,、,GIST,、,MPN,吉菲替尼（易瑞莎）,EGFR,：,NSCLC,、,CRC,埃罗替尼（国产特罗凯）,EGFR,：,NSCLC,靶向药品开发思路,（,6,）肿瘤基因表达谱,肿瘤基因表达及其治疗策略,Cutoff:30%,GCB,：,CD10+,或,CD10-/Bcl6+/MUM1-,Non-GCB,：其它类型,Hans CP,et,al.,Blood,2004;103:275-282.,Rosenwald A,et al.,N Engl J Med,.2002;346(25):1937-1947.,典型应用：弥漫大,B,细胞淋巴瘤的分子亚型和预后、治疗,3.,肿瘤治疗,如何治疗肿瘤？,早发现、早诊断、早治疗,良性肿瘤：单纯切除,恶性肿瘤：,癌：,局部扩大切除,区域淋巴结清扫,全器官摘除,区域淋巴结清扫,改良根治术,手术化疗放疗靶向治疗,+,免疫治疗,肉瘤：手术放疗化疗？,白血病、淋巴瘤：化疗,+HSCT,原则：,NCCN,（美国国家综合癌症网络）、,ASCO,（美国临床肿瘤学会）指南，分期标准,AJCC,4.,肿瘤发生的分子基础,肿瘤生长与增殖信号转导过程,自给自足的生长因子,：常因原癌基因激活所致。

对生长抑制信号不敏感,逃逸凋亡,DNA,修复缺陷,无限复制,持续血管发生,侵袭与转移,细胞周期调控,RB,控制正常细胞周期,下游转导依赖,RAS,6.,肿瘤发生的分子机制,癌基因（,oncogene,）,病毒癌基因,(viral oncogene,v-onc),：能引起动物或体外细胞发生转化的逆转录病毒,RNA,序列Rous,首先对病毒致癌问题进行了研究，在,1911,年发现了能引起鸟类成纤维细胞转化的病毒，这种病毒命名为,Rous,肉瘤病毒Rous,因此于,1966,年,(,是年,85,岁,),荣获诺贝尔奖细胞癌基因,(cellular oncogene,c-onc),：在正常细胞基因组中发现与病毒癌基因类似的,DNA,序列，称为原癌基因,(proto-oncogene),，原癌基因发生某些异常时，能使细胞发生转化，则为,c-onc,原癌基因存在于正常细胞中；,原癌基因产物对细胞生长与增殖起调控作用1989,年,Harold Varmus,和,Michael Bishop,因发现原癌基因致瘤机制荣获诺贝尔奖原癌基因激活,点突变,(point mutation),：,Ras,基因,12,号密码子突变,GGCGTC,甘氨酸缬氨酸,原癌基因激活,(2),基因扩增,(gene amplification),：,神经母细胞,N-myc,基因,形成双微体,出现均质染色区,原癌基因激活,(3),染色体易位,(chromosomal translocation),：,原癌基因过度表达,Burkitt,淋巴瘤,8,号染色体,c-myc,转位至,14,号染色体,Ig,区域。

产生致瘤蛋白,慢粒,9,号染色体,abl,基因转位至,22,号染色体,bcr,位点，形成,BCR-ABL,融合基因（费城染色体）,Selected Oncogenes,Their Mode of Activation,and Associated Human Tumors,Category,Protooncogene,Mode of Activation,Associated Human Tumor,Growth Factors,PDGF-chain,SIS,Overexpression,Astrocytome,Osteosarcoma,Fibroblast growth factors,HST-1,Overexpression,Stomach cancer,INT-2,Amplification,Bladder cancer,Breast cancer,Melanoma,TGF,TGF,Overexpression,Astrocytomas,Hepatocellular carcinomas,HGF,HGF,Overexpression,Thyroid cancer,Growth Factor Receptors,EGF-receptor family,ERB-B1(ECFR),Overexpression,Squamous cell carcinomas of lung,gliomas,ERB-B2,Amplification,Breast and ovarian cancers,CSF-1 receptor,FMS,Point mutation,Leukemia,Receptor for neurotrophic factors,RET,Point mutation,Multiple endocrine neoplasia 2A and B,familial medullary thyroid carcinomas,PDGF receptor,PDGF-R,Overexpression,Gliomas,Receptor for stem cell(steel)factor,KIT,Point mutation,Gastrointestinal stromal tumors and other soft tissue tumors,Selected Oncogenes,Their Mode of Activation,and Associated Human Tumors(continued),Category,Protooncogene,Mode of Activation,Associated Human Tumor,Proteins Involved in Signal Transduction,GTP-binding,K-RAS,Point mutation,Colon,lung,and pancreatic tumors,H-RAS,Point mutation,Bladder and kidney tumors,N-RAS,Point mutation,Melanomas,hematologic malignancies,Nonreceptor tyrosine kinase,ABL,Translocation,Chronic myeloid leukemia,Acute lymphoblastic leukemia,RAS signal transduction,BRAF,Point mutation,Melanomas,WNT signal transduction,-catenin,Point mutation,Overexpression,Hepatoblastomas,hepatocellular carcinoma,Nuclear Regulatory Proteins,Transcriptional activators,C-MYC,Translocation,Burkitt lymphoma,N-MYC,Amplification,Neuroblastoma,small cell carcinoma of lung,L-MYC,Amplification,Small cell carcinoma of lung,Cell-Cycle Regulators,Cyclins,CYCLIN D,Translocation,Mantle cell lymphoma,Amplification,Breast and esophageal cancers,CYCLIN E,Overexpression,Breast cancer,Cyclin-dependent kinase,CDK4,Amplification or point mutation,Glioblastoma,melanoma,sarcoma,7.,肿瘤抑制基因,肿瘤抑制基因,(tumor suppressor gene),：在正常细胞生长与增殖调控中起作用，限制细胞生长，功能丧失导致细胞转化。

1974,年,Knudson“,两次打击假说”,(tow hit hypothesis),即等位基因的两个拷贝均被灭活肿瘤抑制基因失活方式：,突变：错义突变,与肿瘤病毒蛋白结合,与癌蛋白结合,肿瘤抑制蛋白不能进入核内发挥作用,视网膜母细胞瘤,Rb,基因失活的“二次打击假说”,The role of Rb in regulating the G1-S checkpoint of the cell cycle.Hypophosphorylated Rb in complex with the E2F transcription factors binds to DNA。