肿瘤瘤肿 瘤瘤良性恶性肿瘤(tumor)Carcinoma癌Sarcoma肉瘤Leukemia白血病癌症(cancer)儿童肿瘤发病率在逐渐升高。儿童肿瘤发病率在逐渐升高。在在5-105-10岁儿童中，恶性肿瘤在岁儿童中，恶性肿瘤在造成死亡病种中排名第一位。造成死亡病种中排名第一位。提高肿瘤防治水平和寻找治疗提高肿瘤防治水平和寻找治疗肿瘤的新方法已成为现代医学肿瘤的新方法已成为现代医学所面临的最大挑战。所面临的最大挑战。 恶性肿瘤:人类死亡的元凶人类死亡的元凶现代医学面临的重要挑战之一现代医学面临的重要挑战之一、多步骤、多步骤治疗多因素多因素肿瘤发病学概论肿瘤发病学概论陈国强1.肿瘤病因学PottP(1775):VolkmanandBell(1870s):Rehn(1880s):YamagiwaandIchikawa(1915):CookJames(1933):ChemicalcarcinogendirectindirectPro-carcinogen童年童年时当当过烟囱清烟囱清扫工的男性患阴囊癌的比率增高工的男性患阴囊癌的比率增高 长期与石蜡油和焦油接触的工人易患皮肤癌期与石蜡油和焦油接触的工人易患皮肤癌 接触苯胺的工人接触苯胺的工人发生泌尿道膀胱生泌尿道膀胱肿瘤瘤 反复用煤焦油涂擦兔耳成功地反复用煤焦油涂擦兔耳成功地诱发了皮肤癌了皮肤癌 证明多种化学致癌物明多种化学致癌物(Benzopyrene)与与动物物肿瘤的关系瘤的关系 烷化剂、亚硝酰胺烷化剂、亚硝酰胺巴豆油、糖精、巴豆油、糖精、苯巴比妥苯巴比妥多环芳香烃、芳香胺类、多环芳香烃、芳香胺类、亚硝胺、黄曲霉素亚硝胺、黄曲霉素IndirectCarcinogenprecarcinigenProximate carcinigenUltimate carcinigencarcinogenDNAadducts潜潜近近终终MetabolicactivationPolycyclic arimatichydrocarbon, PAHDNAdamagedetoxicationDNArepairmalignantTobacco-specificnitrosamines,TSNAAromaticaminesTobaccoEllermannandBang(1908,丹麦):chickenleukemiaRous(1911，美国):Shope(1933):Burkitt(1962):viruslymphomaEpsteinandbarr(1964):EBvirusviruscarcinogenDNAvirusRNAvirus无无细胞的胞的滤液与液与恶性性肿瘤有病因学上的关系瘤有病因学上的关系 用用滤液成功地液成功地诱发了了鸡的肉瘤的肉瘤将病毒所致的野兔乳将病毒所致的野兔乳头状瘤状瘤进行皮下移植行皮下移植实验，发生浸生浸润性性鳞癌癌 发现病毒可以引起淋巴瘤病毒可以引起淋巴瘤在在Burkitt淋巴瘤淋巴瘤细胞培养液中胞培养液中发现EB病毒病毒Roussarcomavirus(RSV)DNAvirus与动物或人类肿瘤有关的致瘤性与动物或人类肿瘤有关的致瘤性NDA病毒：病毒：vDNA病毒一般没有细胞内同源物乳-多-空病毒类腺病毒类疱疹病毒类乙型肝炎病毒类痘病毒类转化蛋白转化蛋白E1A、E1BSV40 T抗原抗原HPV16、HPV18 E6、E7转化蛋白转化蛋白Rbp53核蛋白核蛋白v病毒的致癌作用发生在病毒进入细胞后复制的早期阶段，相关的瘤基因多整合至宿主细胞DNA上。共同特征：共同特征：某些NDA病毒在染色体上的定位具有倾向性，往往表现为累及多个染色体的位点，可能涉及到染色体的脆性部位和原瘤基因的位点.DNAviruspermissivecellDNAvirusDNAvirusDNAvirusDNAvirusDNAvirusDNAvirusDNAvirusDNAvirusDNAviruslyticinfectionDNAvirusDNAvirusabortiveinfectionNon-permissivecell早期:产生转化蛋白晚期:形成病毒颗粒细胞裂解基因组整合到细胞的DNA中，使细胞发生转化retrovirusRNALTRgagpolenvLTRRNAvirusRNAprovirusLTRgagpolenvLTR123LTRLTR123gagpolenvNon-defective virustheRoussarcomavirus(RSV):theRSVtransforminggene(designatedv-src)washomologoustoahostcellulargene(c-src)60KD、具有酪氨酸激酶活性的PP60蛋白，参与信号转导途径，与多种肿瘤发病相关C-srcLTRgagpolenvLTR123LTRgagpolLTR123defective virusRetinoblastomathemostcommonintraocularcancerinchildrenIncidence：1of13,500-25,000livebirthsSites:unilateral(20%hereditary),bilateral(allhereditary)Onsettime:Bilateral-12m,unilateral-18m,Most(90%): 1,000,000 Proteins脱氧核糖核苷酸组成多聚核苷酸链，两条链互相盘绕形成双螺旋磷酸核糖腺嘌呤A碱基碱基碱基碱基胞嘧啶C碱基对核糖-磷酸骨架氢键3端羟基5端磷酸胸腺嘧啶T鸟嘌呤G2.肿瘤相关基因DNArecombinanttechniquesDNAtransfectionOncogeneKaryotypicanalysisMolecularcloneDNArecombinanttechniquesDNAtransfectionKaryotypicanalysisMolecularcloneOncogenehomogeneouslystainingregionsHSRTumorsuppressorhereditarynonpolyposiscolorectalcancer(HNPCC)syndromesmutator/DNA-mismatchrepair-involvedgenesTumorsuppressormutator/DNA-mismatchrepair-involvedgenesOncogeneOncogeneretrovirusRNALTRgagpolenvLTRRNAvirusRNARous(1911，美国):1950s:电镜的应用RNAvirus用用滤液成功地液成功地诱发了了鸡的肉瘤的肉瘤Roussarcomavirus(RSV)1966:Nobel奖theRSVtransforminggene(designatedv-src)homologoustoahostcellulargene(c-src)1989:BishopandVarmas,Nobel奖Oncogenes are essential for human life activity, whose normal function is to control cellular growth and differentiation /apoptosis or, in different terms, cell birth and cell death. Correspondingly, their structural and/or functional alterations lead uncontrolled cellular growth and abnormal differentiation/apoptosis 生生长因子因子生生长因子受体因子受体信号信号传递分子分子转录因子因子Mechanisms of Oncogene ActivationMechanisms of Oncogene Activation ORFRSProto-oncogeneORFRSORFRSORFRSmutationamplificationORFRSRSRe-arrangementdeletionPoint mutationRas15-20%K-rasN-rasH-rascarcinomas30%:lungadenocarcinomas50%coloncarcinomas90%:pancreaticcarcinomasBloodmalignanciesExon 12insersionPartialkaryotypesoftrypsin-Giemsa-bandedmetaphasecellsdepictingnonrandomchromosomalrearrangementsobservedinlymphoidmalignantdiseases.t(4;11)(q21;q23)inALLt(1;19)(q21;p13)inpre-BcellALLt(8;14)(q24;q32)inB-cellALLandBurkittslymphomainv(14)9q11q32)inT-cellleukemia/lymphomat(8;14)(q24;q11)inT-cellleukemia/lymphomat(14;18)(q32;q21)inB-cellNHL8q24 :MYCgene18q21: BCL214q32 : IGHq32q32q32141414q32q32q32141414慢性粒细胞性白血病（慢性粒细胞性白血病（CML）Bcr-ablBcr-abl酪氨酸激酶激酶底物3T3cellsTumorsuppressorTumorsuppressorDNArecombinanttechniquesDNAtransfectionKaryotypicanalysisMolecularcloneOncogenehomogeneouslystainingregionsHSRhereditarynonpolyposiscolorectalcancer(HNPCC)syndromesmutator/DNA-mismatchrepair-involvedgenesmutator/DNA-mismatchrepair-involvedgenesOncogeneTumorsuppressorKnudson：two hit hypothesisRetinoblastomathemostcommonintraocularcancerinchildrenIncidence：1of13,500-25,000livebirthsSites:unilateral(20%hereditary),bilateral(allhereditary)Onsettime:Bilateral-12m,unilateral-18m,Most(90%):3y1978年Francke13q141983年Cavenee等lossofheterozygosity，LOH染色体13q14处的DNA标志。q1986年，美国三个实验室分别独立克隆了该基因RbS SM MG2G2G1G1CellcycleQuiescence(G0)G2G2G1G1S SM MCellcyclecyclinscyclinsCDKcyclinsCDKCDKIG2G2G1G1S SM MCellcycleDPE2FDNA synthesis-related genesE2FRbPE2FCyclinD1CDK4RbPPPPPRbPPPPP等位基因缺失:视网膜母细胞瘤、骨肉瘤、小细胞肺癌、非小细胞肺癌、膀胱癌、乳腺癌、软组织肉瘤、肝癌等肿瘤Rb基因的异常基因突变：以肺癌、乳腺癌、骨肉瘤、软组织肉瘤出现率高，从1550不等，主要集中于外显子1317上。在小细胞肺癌中Rb基因异常可达47，骨肉瘤可达43，乳腺癌可达32。在原发性肝癌可达18。tumor suppressor generecessive oncogeneantioncogeneOncogene+-该恶性肿瘤的相应正常组织中该基因必须正常表达；该恶性肿瘤中这种基因应有功能失活或结构改变或表达缺陷；导人基因异常的肿瘤细胞内可部分或全部改变其恶性表型chemicalphysicalvirustumor suppressor geneOncogene+-Geneschemicalphysicalvirustumor suppressor geneOncogene+-Genes？growthdifferentiationdeath?growthdifferentiationdeathchemicalphysicalvirustumor suppressor geneOncogene+-Genes谢谢