大學(xué)課件：腫瘤的病理生理學(xué)

腫瘤腫瘤病理生理學(xué)教研室腫瘤腫瘤病理生理學(xué)教研室良性惡性腫瘤(tumor)Carcinoma癌Sarcoma肉瘤Leukemia白血病癌癥(cancer)良性惡性腫瘤(tumor)CarcinomaSarcoma大學(xué)課件：腫瘤的病理生理學(xué)兒童腫瘤發(fā)病率在逐漸升高。在5-10歲兒童中，惡性腫瘤在造成死亡病種中排名第一位。提高腫瘤防治水平和尋找治療腫瘤的新方法已成為現(xiàn)代醫(yī)學(xué)所面臨的最大挑戰(zhàn)。惡性腫瘤:人類死亡的元兇現(xiàn)代醫(yī)學(xué)面臨的重要挑戰(zhàn)之一兒童腫瘤發(fā)病率在逐漸升高。在5-10歲兒童中，惡性腫瘤在造成、多步驟治療多因素、多步驟治療多因素腫瘤發(fā)病學(xué)概論1.腫瘤病因?qū)W腫瘤發(fā)病學(xué)概論1.腫瘤病因?qū)WPottP(1775):VolkmanandBell(1870’s):Rehn(1880’s):YamagiwaandIchikawa(1915):CookJames(1933):ChemicalcarcinogendirectindirectPro-carcinogen童年時當(dāng)過煙囪清掃工的男性患陰囊癌的比率增高長期與石蠟油和焦油接觸的工人易患皮膚癌接觸苯胺的工人發(fā)生泌尿道膀胱腫瘤反復(fù)用煤焦油涂擦兔耳成功地誘發(fā)了皮膚癌證明多種化學(xué)致癌物(Benzopyrene)與動物腫瘤的關(guān)系烷化劑、亞硝酰胺巴豆油、糖精、苯巴比妥多環(huán)芳香烴、芳香胺類、亞硝胺、黃曲霉素PottP(1775):VolkmanandBellIndirectCarcinogenprecarcinigenProximatecarcinigenUltimatecarcinigencarcinogen

DNAadducts潛近終IndirectCarcinogenprecarcinigMetabolicactivationPolycyclicarimatichydrocarbon,PAHDNAdamagedetoxicationDNArepairmalignantTobacco-specificnitrosamines,TSNAAromaticaminesTobaccoMetabolicactivationPolycyclicEllermannandBang(1908,丹麥):chickenleukemiaRous(1911，美國):Shope(1933):Burkitt(1962):viruslymphomaEpsteinandbarr(1964):EBvirusviruscarcinogenDNAvirusRNAvirus無細(xì)胞的濾液與惡性腫瘤有病因?qū)W上的關(guān)系用濾液成功地誘發(fā)了雞的肉瘤

將病毒所致的野兔乳頭狀瘤進(jìn)行皮下移植實(shí)驗(yàn)，發(fā)生浸潤性鱗癌發(fā)現(xiàn)病毒可以引起淋巴瘤在Burkitt淋巴瘤細(xì)胞培養(yǎng)液中發(fā)現(xiàn)EB病毒Roussarcomavirus(RSV)EllermannandBang(1908,丹麥):DNAvirus與動物或人類腫瘤有關(guān)的致瘤性NDA病毒：DNA病毒一般沒有細(xì)胞內(nèi)同源物乳-多-空病毒類腺病毒類皰疹病毒類乙型肝炎病毒類痘病毒類轉(zhuǎn)化蛋白E1A、E1BSV40T抗原HPV16、HPV18E6、E7轉(zhuǎn)化蛋白Rbp53核蛋白病毒的致癌作用發(fā)生在病毒進(jìn)入細(xì)胞后復(fù)制的早期階段，相關(guān)的瘤基因多整合至宿主細(xì)胞DNA上。共同特征：某些NDA病毒在染色體上的定位具有傾向性，往往表現(xiàn)為累及多個染色體的位點(diǎn)，可能涉及到染色體的脆性部位和原瘤基因的位點(diǎn).DNA與動物或人類腫瘤有關(guān)的致瘤性NDA病毒：乳-多-空病毒DNAviruspermissivecellDNAvirusDNAvirusDNAvirusDNAvirusDNAvirusDNAvirusDNAvirusDNAvirusDNAviruslyticinfectionDNAvirusDNAvirusabortiveinfectionNon-permissivecell早期:產(chǎn)生轉(zhuǎn)化蛋白晚期:形成病毒顆粒細(xì)胞裂解基因組整合到細(xì)胞的DNA中，使細(xì)胞發(fā)生轉(zhuǎn)化DNApermissivecellDNADNADNADNAretrovirusRNALTRgagpolenvLTRRNAvirusRNAretrovirusRNALTRgagpolenvLTRRNprovirusprovirusLTRgagpolenvLTR123LTRLTR123gagpolenvNon-defectivevirustheRoussarcomavirus(RSV):theRSVtransforminggene(designatedv-src)washomologoustoahostcellulargene(c-src)60KD、具有酪氨酸激酶活性的PP60蛋白，參與信號轉(zhuǎn)導(dǎo)途徑，與多種腫瘤發(fā)病相關(guān)

C-srcLTRgagpolenvLTR123LTRLTR123gagLTRgagpolenvLTR123LTRgagpolLTR123defectivevirusLTRgagpolenvLTR123LTRgagpolLTRetinoblastoma

themostcommonintraocularcancerinchildrenIncidence：1of13,500-25,000livebirthsSites:unilateral(20%hereditary),bilateral(allhereditary)Onsettime:Bilateral-12m,unilateral-18m,Most(90%):<3yRetinoblastoma種族分布差異家族聚集現(xiàn)象遺傳缺陷遺傳因素流行病學(xué)分析家系分析細(xì)胞遺傳學(xué)研究分子遺傳學(xué)研究染色體水平分子/基因水平種族分布差異家族聚集現(xiàn)象遺傳缺陷遺傳因素流行病學(xué)分析家系分析?chemicalphysicalvirusHugoDeVriesandBoveri（1914）MutationaltheoryOswaldAveryDNA-geneticcarrierJamesWatsonandFrancisCrick(1953)MendalMorganGeorgeBeadle/EdwardTatum(1940s)分子腫瘤學(xué)時代themolecularpathogenesisofhumancancerisduetostructuraland/orfunctionalalterationsofspecificgenes?chemicalphysicalvirusHugoDeRenatoDulbecco1986年發(fā)表于《Science》雜志231卷1055—1056頁的短文“腫瘤研究的轉(zhuǎn)折點(diǎn)：人類基因組測序”中指出：

“如果我們想更多地了解腫瘤，我們從現(xiàn)在起必須關(guān)注細(xì)胞的基因組?！瓘哪膫€物種著手努力？如果我們想理解人類腫瘤，那就應(yīng)從人類開始……。人類腫瘤研究將因?qū)NA的詳細(xì)知識而得到巨大推動?！盧enatoDulbecco1986年發(fā)表于《SRNAProteinsYYModifiedProteinsDNABiologicalFunctionTranscriptionTranslationPost-TranslationModificationGenomeTranscriptomeProteomex5to50functionallinksperprotein~30,000Genes>1,000,000Proteins脫氧核糖核苷酸組成多聚核苷酸鏈，兩條鏈互相盤繞形成雙螺旋磷酸核糖腺嘌呤A堿基堿基堿基堿基胞嘧啶C堿基對核糖-磷酸骨架氫鍵3’端羥基5’端磷酸胸腺嘧啶T鳥嘌呤GRNAProteinsYYModifiedDNABiolo2.腫瘤相關(guān)基因2.腫瘤相關(guān)基因DNArecombinanttechniquesDNAtransfectionOncogeneKaryotypicanalysisMolecularcloneDNArecombinanttechniquesDNADNArecombinanttechniquesDNAtransfectionKaryotypicanalysisMolecularcloneOncogenehomogeneouslystainingregions[HSR]Tumorsuppressorhereditarynonpolyposiscolorectalcancer(HNPCC)syndromesmutator/DNA-mismatchrepair-involvedgenesTumorsuppressormutator/DNA-mismatchrepair-involvedgenesOncogeneOncogeneDNArecombinanttechniquesDNAretrovirusRNALTRgagpolenvLTRRNAvirusRNAretrovirusRNALTRgagpolenvLTRRNRous(1911，美國):1950s’:電鏡的應(yīng)用RNAvirus用濾液成功地誘發(fā)了雞的肉瘤

Roussarcomavirus(RSV)1966’:Nobel獎theRSVtransforminggene(designatedv-src)homologoustoahostcellulargene(c-src)1989:BishopandVarmas,Nobel獎Oncogenesareessentialforhumanlifeactivity,whosenormalfunctionistocontrolcellulargrowthanddifferentiation/apoptosisor,indifferentterms,cellbirthandcelldeath.Correspondingly,theirstructuraland/orfunctionalalterationsleaduncontrolledcellulargrowthandabnormaldifferentiation/apoptosisRous(1911，美國):1950s’:電鏡的應(yīng)用RNA生長因子生長因子受體信號傳遞分子轉(zhuǎn)錄因子生長因子生長因子受體信號傳遞分子轉(zhuǎn)錄因子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-慢性粒細(xì)胞性白血?。–ML）慢性粒細(xì)胞性白血病（CML）大學(xué)課件：腫瘤的病理生理學(xué)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大學(xué)課件：腫瘤的病理生理學(xué)1978年Francke13q141983年Cavenee等lossofheterozygosity，LOH染色體13q14處的DNA標(biāo)志。1986年，美國三個實(shí)驗(yàn)室分別獨(dú)立克隆了該基因Rb1978年1983年Cavenee等1986年，美國三個實(shí)驗(yàn)SMG2G1CellcycleQuiescence(G0)SMG2G1CellcycleQuiescenceG2G1SMCellcyclecyclinscyclinsCDKcyclinsCDKCDKIG2G1SMCellcyclecyclinscyclinsG2G1SMCellcycleDPE2FDNAsynthesis-relatedgenesE2FRbPE2FCyclinD1CDK4RbPPPPPRbPPPPPG2G1SMCellcycleDPE2FDNAsynth等位基因缺失:視網(wǎng)膜母細(xì)胞瘤、骨肉瘤、小細(xì)胞肺癌、非小細(xì)胞肺癌、膀胱癌、乳腺癌、軟組織肉瘤、肝癌等腫瘤Rb基因的異常基因突變：以肺癌、乳腺癌、骨肉瘤、軟組織肉瘤出現(xiàn)率高，從15％～50％不等，主要集中于外顯子13～17上。在小細(xì)胞肺癌中Rb基因異?？蛇_(dá)47％，骨肉瘤可達(dá)43％，乳腺癌可達(dá)32％。在原發(fā)性肝癌可達(dá)18％。等位基因缺失:視網(wǎng)膜母細(xì)胞瘤、骨肉瘤、小細(xì)胞肺癌、非小細(xì)胞肺tumorsuppressorgenerecessiveoncogeneantioncogeneOncogene+-①該惡性腫瘤的相應(yīng)正常組織中該基因必須正常表達(dá)；②該惡性腫瘤中這種基因應(yīng)有功能失活或結(jié)構(gòu)改變或表達(dá)缺陷；③導(dǎo)人基因異常的腫瘤細(xì)胞內(nèi)可部分或全部改變其惡性表型tumorsuppressorgenerecessivechemicalphysicalvirustumorsuppressorgeneOncogene+-GeneschemicalphysicalvirustumorsupchemicalphysicalvirustumorsuppressorgeneOncogene+-Genes？chemicalphysicalvirustumorsupgrowthdifferentiationdeath???growthdifferentiationdeath???growthdifferentiationdeathchemicalphysicalvirustumorsuppressorgeneOncogene+-Genesgrowthdifferentiationdeathchem謝謝謝謝腫瘤腫瘤病理生理學(xué)教研室腫瘤腫瘤病理生理學(xué)教研室良性惡性腫瘤(tumor)Carcinoma癌Sarcoma肉瘤Leukemia白血病癌癥(cancer)良性惡性腫瘤(tumor)CarcinomaSarcoma大學(xué)課件：腫瘤的病理生理學(xué)兒童腫瘤發(fā)病率在逐漸升高。在5-10歲兒童中，惡性腫瘤在造成死亡病種中排名第一位。提高腫瘤防治水平和尋找治療腫瘤的新方法已成為現(xiàn)代醫(yī)學(xué)所面臨的最大挑戰(zhàn)。惡性腫瘤:人類死亡的元兇現(xiàn)代醫(yī)學(xué)面臨的重要挑戰(zhàn)之一兒童腫瘤發(fā)病率在逐漸升高。在5-10歲兒童中，惡性腫瘤在造成、多步驟治療多因素、多步驟治療多因素腫瘤發(fā)病學(xué)概論1.腫瘤病因?qū)W腫瘤發(fā)病學(xué)概論1.腫瘤病因?qū)WPottP(1775):VolkmanandBell(1870’s):Rehn(1880’s):YamagiwaandIchikawa(1915):CookJames(1933):ChemicalcarcinogendirectindirectPro-carcinogen童年時當(dāng)過煙囪清掃工的男性患陰囊癌的比率增高長期與石蠟油和焦油接觸的工人易患皮膚癌接觸苯胺的工人發(fā)生泌尿道膀胱腫瘤反復(fù)用煤焦油涂擦兔耳成功地誘發(fā)了皮膚癌證明多種化學(xué)致癌物(Benzopyrene)與動物腫瘤的關(guān)系烷化劑、亞硝酰胺巴豆油、糖精、苯巴比妥多環(huán)芳香烴、芳香胺類、亞硝胺、黃曲霉素PottP(1775):VolkmanandBellIndirectCarcinogenprecarcinigenProximatecarcinigenUltimatecarcinigencarcinogen

DNAadducts潛近終IndirectCarcinogenprecarcinigMetabolicactivationPolycyclicarimatichydrocarbon,PAHDNAdamagedetoxicationDNArepairmalignantTobacco-specificnitrosamines,TSNAAromaticaminesTobaccoMetabolicactivationPolycyclicEllermannandBang(1908,丹麥):chickenleukemiaRous(1911，美國):Shope(1933):Burkitt(1962):viruslymphomaEpsteinandbarr(1964):EBvirusviruscarcinogenDNAvirusRNAvirus無細(xì)胞的濾液與惡性腫瘤有病因?qū)W上的關(guān)系用濾液成功地誘發(fā)了雞的肉瘤

將病毒所致的野兔乳頭狀瘤進(jìn)行皮下移植實(shí)驗(yàn)，發(fā)生浸潤性鱗癌發(fā)現(xiàn)病毒可以引起淋巴瘤在Burkitt淋巴瘤細(xì)胞培養(yǎng)液中發(fā)現(xiàn)EB病毒Roussarcomavirus(RSV)EllermannandBang(1908,丹麥):DNAvirus與動物或人類腫瘤有關(guān)的致瘤性NDA病毒：DNA病毒一般沒有細(xì)胞內(nèi)同源物乳-多-空病毒類腺病毒類皰疹病毒類乙型肝炎病毒類痘病毒類轉(zhuǎn)化蛋白E1A、E1BSV40T抗原HPV16、HPV18E6、E7轉(zhuǎn)化蛋白Rbp53核蛋白病毒的致癌作用發(fā)生在病毒進(jìn)入細(xì)胞后復(fù)制的早期階段，相關(guān)的瘤基因多整合至宿主細(xì)胞DNA上。共同特征：某些NDA病毒在染色體上的定位具有傾向性，往往表現(xiàn)為累及多個染色體的位點(diǎn)，可能涉及到染色體的脆性部位和原瘤基因的位點(diǎn).DNA與動物或人類腫瘤有關(guān)的致瘤性NDA病毒：乳-多-空病毒DNAviruspermissivecellDNAvirusDNAvirusDNAvirusDNAvirusDNAvirusDNAvirusDNAvirusDNAvirusDNAviruslyticinfectionDNAvirusDNAvirusabortiveinfectionNon-permissivecell早期:產(chǎn)生轉(zhuǎn)化蛋白晚期:形成病毒顆粒細(xì)胞裂解基因組整合到細(xì)胞的DNA中，使細(xì)胞發(fā)生轉(zhuǎn)化DNApermissivecellDNADNADNADNAretrovirusRNALTRgagpolenvLTRRNAvirusRNAretrovirusRNALTRgagpolenvLTRRNprovirusprovirusLTRgagpolenvLTR123LTRLTR123gagpolenvNon-defectivevirustheRoussarcomavirus(RSV):theRSVtransforminggene(designatedv-src)washomologoustoahostcellulargene(c-src)60KD、具有酪氨酸激酶活性的PP60蛋白，參與信號轉(zhuǎn)導(dǎo)途徑，與多種腫瘤發(fā)病相關(guān)

C-srcLTRgagpolenvLTR123LTRLTR123gagLTRgagpolenvLTR123LTRgagpolLTR123defectivevirusLTRgagpolenvLTR123LTRgagpolLTRetinoblastoma

themostcommonintraocularcancerinchildrenIncidence：1of13,500-25,000livebirthsSites:unilateral(20%hereditary),bilateral(allhereditary)Onsettime:Bilateral-12m,unilateral-18m,Most(90%):<3yRetinoblastoma種族分布差異家族聚集現(xiàn)象遺傳缺陷遺傳因素流行病學(xué)分析家系分析細(xì)胞遺傳學(xué)研究分子遺傳學(xué)研究染色體水平分子/基因水平種族分布差異家族聚集現(xiàn)象遺傳缺陷遺傳因素流行病學(xué)分析家系分析?chemicalphysicalvirusHugoDeVriesandBoveri（1914）MutationaltheoryOswaldAveryDNA-geneticcarrierJamesWatsonandFrancisCrick(1953)MendalMorganGeorgeBeadle/EdwardTatum(1940s)分子腫瘤學(xué)時代themolecularpathogenesisofhumancancerisduetostructuraland/orfunctionalalterationsofspecificgenes?chemicalphysicalvirusHugoDeRenatoDulbecco1986年發(fā)表于《Science》雜志231卷1055—1056頁的短文“腫瘤研究的轉(zhuǎn)折點(diǎn)：人類基因組測序”中指出：

“如果我們想更多地了解腫瘤，我們從現(xiàn)在起必須關(guān)注細(xì)胞的基因組?！瓘哪膫€物種著手努力？如果我們想理解人類腫瘤，那就應(yīng)從人類開始……。人類腫瘤研究將因?qū)NA的詳細(xì)知識而得到巨大推動?！盧enatoDulbecco1986年發(fā)表于《SRNAProteinsYYModifiedProteinsDNABiologicalFunctionTranscriptionTranslationPost-TranslationModificationGenomeTranscriptomeProteomex5to50functionallinksperprotein~30,000Genes>1,000,000Proteins脫氧核糖核苷酸組成多聚核苷酸鏈，兩條鏈互相盤繞形成雙螺旋磷酸核糖腺嘌呤A堿基堿基堿基堿基胞嘧啶C堿基對核糖-磷酸骨架氫鍵3’端羥基5’端磷酸胸腺嘧啶T鳥嘌呤GRNAProteinsYYModifiedDNABiolo2.腫瘤相關(guān)基因2.腫瘤相關(guān)基因DNArecombinanttechniquesDNAtransfectionOncogeneKaryotypicanalysisMolecularcloneDNArecombinanttechniquesDNADNArecombinanttechniquesDNAtransfectionKaryotypicanalysisMolecularcloneOncogenehomogeneouslystainingregions[HSR]Tumorsuppressorhereditarynonpolyposiscolorectalcancer(HNPCC)syndromesmutator/DNA-mismatchrepair-involvedgenesTumorsuppressormutator/DNA-mismatchrepair-involvedgenesOncogeneOncogeneDNArecombinanttechniquesDNAretrovirusRNALTRgagpolenvLTRRNAvirusRNAretrovirusRNALTRgagpolenvLTRRNRous(1911，美國):1950s’:電鏡的應(yīng)用RNAvirus用濾液成功地誘發(fā)了雞的肉瘤

Roussarcomavirus(RSV)1966’:Nobel獎theRSVtransforminggene(designatedv-src)homologoustoahostcellulargene(c-src)1989:BishopandVarmas,Nobel獎Oncogenesareessentialforhumanlifeactivity,whosenormalfunctionistocontrolcellulargrowthanddifferentiation/apoptosisor,indifferentterms,cellbirthandcelldeath.Correspondingly,theirstructuraland/orfunctionalalterationsleaduncontrolledcellulargrowthandabnormaldifferentiation/apoptosisRous(1911，美國):1950s’:電鏡的應(yīng)用RNA生長因子生長因子受體信號傳遞分子轉(zhuǎn)錄因子生長因子生長因子受體信號傳遞分子轉(zhuǎn)錄因子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-慢性粒細(xì)胞性白血?。–ML）慢性粒細(xì)胞性白血?。–ML）大學(xué)課件：腫瘤的病理生理學(xué)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