大学课件：肿瘤的病理生理学

肿瘤肿瘤病理生理学教研室肿瘤肿瘤病理生理学教研室良性恶性肿瘤(tumor)Carcinoma癌Sarcoma肉瘤Leukemia白血病癌症(cancer)良性恶性肿瘤(tumor)CarcinomaSarcoma大学课件：肿瘤的病理生理学儿童肿瘤发病率在逐渐升高。在5-10岁儿童中，恶性肿瘤在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肿瘤的新方法已成为现代医学所面临的最大挑战。恶性肿瘤:人类死亡的元凶现代医学面临的重要挑战之一儿童肿瘤发病率在逐渐升高。在5-10岁儿童中，恶性肿瘤在造成、多步骤治疗多因素、多步骤治疗多因素肿瘤发病学概论1.肿瘤病因学肿瘤发病学概论1.肿瘤病因学PottP(1775):VolkmanandBell(1870’s):Rehn(1880’s):YamagiwaandIchikawa(1915):CookJames(1933):ChemicalcarcinogendirectindirectPro-carcinogen童年时当过烟囱清扫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接触苯胺的工人发生泌尿道膀胱肿瘤反复用煤焦油涂擦兔耳成功地诱发了皮肤癌证明多种化学致癌物(Benzopyrene)与动物肿瘤的关系烷化剂、亚硝酰胺巴豆油、糖精、苯巴比妥多环芳香烃、芳香胺类、亚硝胺、黄曲霉素PottP(1775):VolkmanandBellIndirectCarcinogenprecarcinigenProximatecarcinigenUltimatecarcinigencarcinogen

DNAadducts潜近终IndirectCarcinogenprecarcinigMetabolicactivationPolycyclicarimatichydrocarbon,PAHDNAdamagedetoxicationDNArepairmalignantTobacco-specificnitrosamines,TSNAAromaticaminesTobaccoMetabolicactivationPolycyclicEllermannandBang(1908,丹麦):chickenleukemiaRous(1911，美国):Shope(1933):Burkitt(1962):viruslymphomaEpsteinandbarr(1964):EBvirusviruscarcinogenDNAvirusRNAvirus无细胞的滤液与恶性肿瘤有病因学上的关系用滤液成功地诱发了鸡的肉瘤

将病毒所致的野兔乳头状瘤进行皮下移植实验，发生浸润性鳞癌发现病毒可以引起淋巴瘤在Burkitt淋巴瘤细胞培养液中发现EB病毒Roussarcomavirus(RSV)EllermannandBang(1908,丹麦):DNAvirus与动物或人类肿瘤有关的致瘤性NDA病毒：DNA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E1A、E1BSV40T抗原HPV16、HPV18E6、E7转化蛋白Rbp53核蛋白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：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.DNA与动物或人类肿瘤有关的致瘤性NDA病毒：乳-多-空病毒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DNApermissivecellDNADNADNADNAretrovirusRNALTRgagpolenvLTRRNAvirusRNAretrovirusRNALTRgagpolenvLTRRNprovirusprovirusLTRgagpolenvLTR123LTRLTR123gagpolenvNon-defectivevirustheRoussarcomavirus(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-srcLTRgagpolenvLTR123LTRLTR123gagLTRgagpolenvLTR123LTRgagpolLTR123defectivevirusLTRgagpolenvLTR123LTRgagpolLTRetinoblastoma

themostcommonintraocularcancerinchildrenIncidence：1of13,500-25,000livebirthsSites:unilateral(20%hereditary),bilateral(allhereditary)Onsettime:Bilateral-12m,unilateral-18m,Most(90%):<3yRetinoblastoma种族分布差异家族聚集现象遗传缺陷遗传因素流行病学分析家系分析细胞遗传学研究分子遗传学研究染色体水平分子/基因水平种族分布差异家族聚集现象遗传缺陷遗传因素流行病学分析家系分析?chemicalphysicalvirusHugoDeVriesandBoveri（1914）MutationaltheoryOswaldAveryDNA-geneticcarrierJamesWatsonandFrancisCrick(1953)MendalMorganGeorgeBeadle/EdwardTatum(1940s)分子肿瘤学时代themolecularpathogenesisofhumancancerisduetostructuraland/orfunctionalalterationsofspecificgenes?chemicalphysicalvirusHugoDeRenatoDulbecco1986年发表于《Science》杂志231卷1055—1056页的短文“肿瘤研究的转折点：人类基因组测序”中指出：

“如果我们想更多地了解肿瘤，我们从现在起必须关注细胞的基因组。……从哪个物种着手努力？如果我们想理解人类肿瘤，那就应从人类开始……。人类肿瘤研究将因对DNA的详细知识而得到巨大推动。”RenatoDulbecco1986年发表于《SRNAProteinsYYModifiedProteinsDNABiologicalFunctionTranscriptionTranslationPost-TranslationModificationGenomeTranscriptomeProteomex5to50functionallinksperprotein~30,000Genes>1,000,000Proteins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GRNAProteinsYYModifiedDNABiolo2.肿瘤相关基因2.肿瘤相关基因DNArecombinanttechniquesDNAtransfectionOncogeneKaryotypicanalysisMolecularcloneDNArecombinanttechniquesDNADNArecombinanttechniquesDNAtransfectionKaryotypicanalysisMolecularcloneOncogenehomogeneouslystainingregions[HSR]Tumorsuppressorhereditarynonpolyposiscolorectalcancer(HNPCC)syndromesmutator/DNA-mismatchrepair-involvedgenesTumorsuppressormutator/DNA-mismatchrepair-involvedgenesOncogeneOncogeneDNArecombinanttechniquesDNAretrovirusRNALTRgagpolenvLTRRNAvirusRNAretrovirusRNALTRgagpolenvLTRRNRous(1911，美国):1950s’:电镜的应用RNAvirus用滤液成功地诱发了鸡的肉瘤

Roussarcomavirus(RSV)1966’:Nobel奖theRSVtransforminggene(designatedv-src)homologoustoahostcellulargene(c-src)1989:BishopandVarmas,Nobel奖Oncogenesareessentialforhumanlifeactivity,whosenormalfunctionistocontrolcellulargrowthanddifferentiation/apoptosisor,indifferentterms,cellbirthandcelldeath.Correspondingly,theirstructuraland/orfunctionalalterationsleaduncontrolledcellulargrowthandabnormaldifferentiation/apoptosisRous(1911，美国):1950s’:电镜的应用RNA生长因子生长因子受体信号传递分子转录因子生长因子生长因子受体信号传递分子转录因子MechanismsofOncogeneActivation

ORFRSProto-oncogeneORFRSORFRSORFRSmutationamplificationORFRSRSRe-arrangementdeletionPointmutationRas15-20%K-rasN-rasH-rascarcinomas30%:lungadenocarcinomas50%coloncarcinomas90%:pancreaticcarcinomasBloodmalignanciesExon12insersionMechanismsofOncogeneActivatPartialkaryotypesoftrypsin-Giemsa-bandedmetaphasecellsdepictingnonrandomchromosomalrearrangementsobservedinlymphoidmalignantdiseases.t(4;11)(q21;q23)inALLt(1;19)(q21;p13)inpre-BcellALLt(8;14)(q24;q32)inB-cellALLandBurkitt'slymphomainv(14)9q11q32)inT-cellleukemia/lymphomat(8;14)(q24;q11)inT-cellleukemia/lymphomat(14;18)(q32;q21)inB-cellNHL8q24:MYCgene18q21:BCL214q32:IGHq32q32q32141414q32q32q32141414Partialkaryotypesoftrypsin-慢性粒细胞性白血病（CML）慢性粒细胞性白血病（CML）大学课件：肿瘤的病理生理学Bcr-abl酪氨酸激酶激酶底物Bcr-abl激酶底物3T3cells3T3cellsTumorsuppressorTumorsuppressorDNArecombinanttechniquesDNAtransfectionKaryotypicanalysisMolecularcloneOncogenehomogeneouslystainingregions[HSR]hereditarynonpolyposiscolorectalcancer(HNPCC)syndromesmutator/DNA-mismatchrepair-involvedgenesmutator/DNA-mismatchrepair-involvedgenesOncogeneTumorsuppressorTumorsuppressorTumorsuppressKnudson：

twohithypothesis

Retinoblastoma

themostcommonintraocularcancerinchildrenIncidence：1of13,500-25,000livebirthsSites:unilateral(20%hereditary),bilateral(allhereditary)Onsettime:Bilateral-12m,unilateral-18m,Most(90%):<3yKnudson：twohithypothesisRe大学课件：肿瘤的病理生理学1978年Francke13q141983年Cavenee等lossofheterozygosity，LOH染色体13q14处的DNA标志。1986年，美国三个实验室分别独立克隆了该基因Rb1978年1983年Cavenee等1986年，美国三个实验SMG2G1CellcycleQuiescence(G0)SMG2G1CellcycleQuiescenceG2G1SMCellcyclecyclinscyclinsCDKcyclinsCDKCDKIG2G1SMCellcyclecyclinscyclinsG2G1SMCellcycleDPE2FDNAsynthesis-relatedgenesE2FRbPE2FCyclinD1CDK4RbPPPPPRbPPPPPG2G1SMCellcycleDPE2FDNAsynth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15％～50％不等，主要集中于外显子13～17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％。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tumorsuppressorgenerecessiveoncogeneantioncogeneOncogene+-①该恶性肿瘤的相应正常组织中该基因必须正常表达；②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；③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tumorsuppressorgenerecessivechemicalphysicalvirustumorsuppressorgeneOncogene+-GeneschemicalphysicalvirustumorsupchemicalphysicalvirustumorsuppressorgeneOncogene+-Genes？chemicalphysicalvirustumorsupgrowthdifferentiationdeath???growthdifferentiationdeath???growthdifferentiationdeathchemicalphysicalvirustumorsuppressorgeneOncogene+-Genesgrowthdifferentiationdeathchem谢谢谢谢肿瘤肿瘤病理生理学教研室肿瘤肿瘤病理生理学教研室良性恶性肿瘤(tumor)Carcinoma癌Sarcoma肉瘤Leukemia白血病癌症(cancer)良性恶性肿瘤(tumor)CarcinomaSarcoma大学课件：肿瘤的病理生理学儿童肿瘤发病率在逐渐升高。在5-10岁儿童中，恶性肿瘤在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肿瘤的新方法已成为现代医学所面临的最大挑战。恶性肿瘤:人类死亡的元凶现代医学面临的重要挑战之一儿童肿瘤发病率在逐渐升高。在5-10岁儿童中，恶性肿瘤在造成、多步骤治疗多因素、多步骤治疗多因素肿瘤发病学概论1.肿瘤病因学肿瘤发病学概论1.肿瘤病因学PottP(1775):VolkmanandBell(1870’s):Rehn(1880’s):YamagiwaandIchikawa(1915):CookJames(1933):ChemicalcarcinogendirectindirectPro-carcinogen童年时当过烟囱清扫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接触苯胺的工人发生泌尿道膀胱肿瘤反复用煤焦油涂擦兔耳成功地诱发了皮肤癌证明多种化学致癌物(Benzopyrene)与动物肿瘤的关系烷化剂、亚硝酰胺巴豆油、糖精、苯巴比妥多环芳香烃、芳香胺类、亚硝胺、黄曲霉素PottP(1775):VolkmanandBellIndirectCarcinogenprecarcinigenProximatecarcinigenUltimatecarcinigencarcinogen

DNAadducts潜近终IndirectCarcinogenprecarcinigMetabolicactivationPolycyclicarimatichydrocarbon,PAHDNAdamagedetoxicationDNArepairmalignantTobacco-specificnitrosamines,TSNAAromaticaminesTobaccoMetabolicactivationPolycyclicEllermannandBang(1908,丹麦):chickenleukemiaRous(1911，美国):Shope(1933):Burkitt(1962):viruslymphomaEpsteinandbarr(1964):EBvirusviruscarcinogenDNAvirusRNAvirus无细胞的滤液与恶性肿瘤有病因学上的关系用滤液成功地诱发了鸡的肉瘤

将病毒所致的野兔乳头状瘤进行皮下移植实验，发生浸润性鳞癌发现病毒可以引起淋巴瘤在Burkitt淋巴瘤细胞培养液中发现EB病毒Roussarcomavirus(RSV)EllermannandBang(1908,丹麦):DNAvirus与动物或人类肿瘤有关的致瘤性NDA病毒：DNA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E1A、E1BSV40T抗原HPV16、HPV18E6、E7转化蛋白Rbp53核蛋白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：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.DNA与动物或人类肿瘤有关的致瘤性NDA病毒：乳-多-空病毒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DNApermissivecellDNADNADNADNAretrovirusRNALTRgagpolenvLTRRNAvirusRNAretrovirusRNALTRgagpolenvLTRRNprovirusprovirusLTRgagpolenvLTR123LTRLTR123gagpolenvNon-defectivevirustheRoussarcomavirus(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-srcLTRgagpolenvLTR123LTRLTR123gagLTRgagpolenvLTR123LTRgagpolLTR123defectivevirusLTRgagpolenvLTR123LTRgagpolLTRetinoblastoma

themostcommonintraocularcancerinchildrenIncidence：1of13,500-25,000livebirthsSites:unilateral(20%hereditary),bilateral(allhereditary)Onsettime:Bilateral-12m,unilateral-18m,Most(90%):<3yRetinoblastoma种族分布差异家族聚集现象遗传缺陷遗传因素流行病学分析家系分析细胞遗传学研究分子遗传学研究染色体水平分子/基因水平种族分布差异家族聚集现象遗传缺陷遗传因素流行病学分析家系分析?chemicalphysicalvirusHugoDeVriesandBoveri（1914）MutationaltheoryOswaldAveryDNA-geneticcarrierJamesWatsonandFrancisCrick(1953)MendalMorganGeorgeBeadle/EdwardTatum(1940s)分子肿瘤学时代themolecularpathogenesisofhumancancerisduetostructuraland/orfunctionalalterationsofspecificgenes?chemicalphysicalvirusHugoDeRenatoDulbecco1986年发表于《Science》杂志231卷1055—1056页的短文“肿瘤研究的转折点：人类基因组测序”中指出：

“如果我们想更多地了解肿瘤，我们从现在起必须关注细胞的基因组。……从哪个物种着手努力？如果我们想理解人类肿瘤，那就应从人类开始……。人类肿瘤研究将因对DNA的详细知识而得到巨大推动。”RenatoDulbecco1986年发表于《SRNAProteinsYYModifiedProteinsDNABiologicalFunctionTranscriptionTranslationPost-TranslationModificationGenomeTranscriptomeProteomex5to50functionallinksperprotein~30,000Genes>1,000,000Proteins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GRNAProteinsYYModifiedDNABiolo2.肿瘤相关基因2.肿瘤相关基因DNArecombinanttechniquesDNAtransfectionOncogeneKaryotypicanalysisMolecularcloneDNArecombinanttechniquesDNADNArecombinanttechniquesDNAtransfectionKaryotypicanalysisMolecularcloneOncogenehomogeneouslystainingregions[HSR]Tumorsuppressorhereditarynonpolyposiscolorectalcancer(HNPCC)syndromesmutator/DNA-mismatchrepair-involvedgenesTumorsuppressormutator/DNA-mismatchrepair-involvedgenesOncogeneOncogeneDNArecombinanttechniquesDNAretrovirusRNALTRgagpolenvLTRRNAvirusRNAretrovirusRNALTRgagpolenvLTRRNRous(1911，美国):1950s’:电镜的应用RNAvirus用滤液成功地诱发了鸡的肉瘤

Roussarcomavirus(RSV)1966’:Nobel奖theRSVtransforminggene(designatedv-src)homologoustoahostcellulargene(c-src)1989:BishopandVarmas,Nobel奖Oncogenesareessentialforhumanlifeactivity,whosenormalfunctionistocontrolcellulargrowthanddifferentiation/apoptosisor,indifferentterms,cellbirthandcelldeath.Correspondingly,theirstructuraland/orfunctionalalterationsleaduncontrolledcellulargrowthandabnormaldifferentiation/apoptosisRous(1911，美国):1950s’:电镜的应用RNA生长因子生长因子受体信号传递分子转录因子生长因子生长因子受体信号传递分子转录因子MechanismsofOncogeneActivation

ORFRSProto-oncogeneORFRSORFRSORFRSmutationamplificationORFRSRSRe-arrangementdeletionPointmutationRas15-20%K-rasN-rasH-rascarcinomas30%:lungadenocarcinomas50%coloncarcinomas90%:pancreaticcarcinomasBloodmalignanciesExon12insersionMechanismsofOncogeneActivatPartialkaryotypesoftrypsin-Giemsa-bandedmetaphasecellsdepictingnonrandomchromosomalrearrangementsobservedinlymphoidmalignantdiseases.t(4;11)(q21;q23)inALLt(1;19)(q21;p13)inpre-BcellALLt(8;14)(q24;q32)inB-cellALLandBurkitt'slymphomainv(14)9q11q32)inT-cellleukemia/lymphomat(8;14)(q24;q11)inT-cellleukemia/lymphomat(14;18)(q32;q21)inB-cellNHL8q24:MYCgene18q21:BCL214q32:IGHq32q32q32141414q32q32q32141414Partialkaryotypesoftrypsin-慢性粒细胞性白血病（CML）慢性粒细胞性白血病（CML）大学课件：肿瘤的病理生理学Bcr-abl酪氨酸激酶激酶底物Bcr-abl激酶底物3T3cells3T3cellsTumorsuppressorTumorsuppressorDNArecombinanttechniquesDNAtransfectionKaryotypicanalysisMolecularcloneOncogenehomogeneouslystainingregions[HSR]hereditarynonpolyposiscolorectalcancer(HNPCC)syndromesmutator/DNA-mismatchrepair-involvedgenesmutator/DNA-mismatchrepair-involvedgenesOncogeneTumorsuppressorTumorsuppressorTumor