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1、医科大学病理学英文课件Section8.EtiologyandpathogenesisoftumorAcquired(environmental) DNA damaging agents chemicals radiation virusesNORMAL CELLDNA DamageSuccessfulDNA repairMutations in the Genome of Somatic cellsFailure of DNA repair Activation of growth-promoting oncogenes Alterations of genes that regulate
2、apoptosis Inactivation of cancer suppressor genes Expression of altered gene products and loss of regulatory gene products Clonal expansion Additional mutations (progression) Heterogeneity Malignant neoplasmF5-97.JPGInherited mutationGenes affecting DNA repair Genes affecting cell growth or apoptosi
3、s获得性DNA损伤因素 (环境因素)： 化学物 电离辐射 病毒正常细胞DNA损伤体细胞基因突变 遗传性DNA突变： DNA修复基因改变 细胞生长或凋亡基因改变DNA修复失败调控凋亡基因的改变促进生长的癌基因活化抑癌基因的失活癌蛋白表达异常抑癌基因产物缺失凋亡失控多克隆性增生单克隆性增生异质化附加突变(转化)附加突变(演进)恶性肿瘤形成图6-47 恶性肿瘤病因和发病的分子机制示意图8.1 Molecular basis of oncogenesis8.1.1Oncogene8.1.1Oncogene1.Protooncogene,oncogeneandproducts1.Protooncogen
4、e,oncogeneandproducts(1)Protooncogene:cellulargenesthat(1)Protooncogene:cellulargenesthat promotepromote normalnormal cellcell growthgrowthandand differentiation,differentiation,existexistininnormalcells,normalcells,intheformofinactivity.intheformofinactivity.(2)Oncogene:derivedfromprotooncogene(2)O
5、ncogene:derivedfromprotooncogenepromotepromoteabnormalgrowth.abnormalgrowth.(3)ModeofprotooncogenesactivationPointmutationChromosomalrearrangementGenelificationpromoterinsertion(4) Products and functions of protooncogenesGrowthfactors:PDGF,FGF,EGFGrowthfactors:PDGF,FGF,EGFGrowthfactors:PDGF,FGF,EGFG
6、rowthfactors:PDGF,FGF,EGFGrowthfactorreceptorsGrowthfactorreceptorsGrowthfactorreceptorsGrowthfactorreceptorsSignal-Signal-Signal-Signal- transducingtransducingtransducingtransducing proteins:proteins:proteins:proteins:rasrasrasrasNuclearNuclearNuclearNuclear regulatoryregulatoryregulatoryregulatory
7、 proteins:proteins:proteins:proteins:mycmycmycmycCellCellCellCellcyclecyclecyclecycleregulatoryregulatoryregulatoryregulatoryproteins:proteins:proteins:proteins:cyclinscyclinscyclinscyclins8.1.2 Tumor suppressor gene1.Concept:1.Concept:cellularcellulargenesgenesthatthatexistexistinin normalnormal ce
8、llscells inhibitinhibit normalnormalgrowthgrowthandandcausecausecellscellstotomalignantmalignanttransformtransformwhenwhentheytheybecomebecomeinactive.inactive.2.Exles:Rb,p53,P16,TGF-,2.Exles:Rb,p53,P16,TGF-, BRCA-1BRCA-1,BRCA-BRCA-2 23.mechanism:allelemutation,3.mechanism:allelemutation, deletion,d
9、eletion,methylationmethylation8.1.3 Genes that regulate apoptosis and DNA repair1.Genes that regulate apoptosis 2. Bcl (B-cell lymphoma)family:3. Bcl-2: inhibit apoptosis4. Bax: induce apoptosis5.2. Genes that regulate DNA repair:8.1.4 Telomeres, telomerase and cancer1.Telomeres1.Telomeresshortingsh
10、ortingisisbelievedbelievedtotobebeaaclockclockthatthatcountscountscellcelldivision,division,isisatumor-suppressivemechanism.atumor-suppressivemechanism.2.Telomerase:2.Telomerase: SustainSustainthethefunctionfunctionofoftelomerestelomeresAbsentfrommostsomaticcellAbsentfrommostsomaticcellIncreasedacti
11、vityofitIncreasedactivityofittumortumor8.1.5 Molecular basis of multistep carcinogenesis MORPHOLOGICAPPEARANCEMOLECULARCHANGENormal epitheliumHyperproliferative epitheliumEarly adenomaIntermediate adenomaLate adenomaCarcinomaLoss or mutation of APC locus on chromosome 5qLoss of DNA methylationMutati
12、on of ras geneon chromosome 12pLoss of tumor suppressoron chromosome 18qLoss of p53 gene on chromosome 17plecular model for the evolution of colorectal cancers through the adenoma-carcinoma sequence.(Based on studies of Fearon ER,Vogelstein B:A genetic model of colorectal carcinogenesis.Cell 61:759,
13、1990.Copyright 1990,Cell Press.)8.2 Environmental factors and their mechanism 8.2.1 Cheminal carcinogenic agents1.Indirect-acting agent(1)Polycyclic hydrocarbons:in fossil fuel or (2)combustion of tabacco in smoking ,relate to the(3)development of skin, lung, stomach carcinoma(2) Aromatic amines and
14、 azo dyes: bladder, hepatocellular carcinoma(3) Aflatoxin: potent hepatocarcinogen(4)Nitrosamines:lung, gastric, esophagus, 2.Direct-actingagents2.Direct-actingagents(1)Alkylatingandacylatingagents:(1)Alkylatingandacylatingagents: anticanceranticancerdrugsdrugscyclophosphamidecyclophosphamide(2)Othe
15、rsarsenicskincarcinoma(2)Othersarsenicskincarcinoma chromiumlungchromiumlungcarcinomacarcinomacadmiumprostatecadmiumprostatecarcinomacarcinomanickellungnickellungcarcinomacarcinoma8.2.2 Physical carcinogenic factors1.1. IonizingIonizing radiation:radiation: X-ray,X-ray, -ray-rayrelatedrelated totole
16、ukemialeukemia,carcinomacarcinomaofofskin,skin,lung,lung,breast,colon.breast,colon.2.UV:skincarcinoma2.UV:skincarcinoma3.Others:3.Others: asbestosasbestos mesotheliomamesothelioma artificialartificial mammarymammarycarcinomacarcinoma8.2.3 Biologic carcigenic agents1.RNAvirus:1.RNAvirus:1.RNAvirus:1.
17、RNAvirus:Transduction/insertionalmutagenesisTransduction/insertionalmutagenesisTransduction/insertionalmutagenesisTransduction/insertionalmutagenesis HTLV-1HTLV-1HTLV-1HTLV-1 : humanhumanhumanhuman TTTT cellcellcellcell leukemia/leukemia/leukemia/leukemia/lymphomalymphomalymphomalymphoma2.DNAvirus:2
18、.DNAvirus:2.DNAvirus:2.DNAvirus:(1)HPV:cervicalsquamouscellcarcinoma(1)HPV:cervicalsquamouscellcarcinoma(1)HPV:cervicalsquamouscellcarcinoma(1)HPV:cervicalsquamouscellcarcinoma(2)(2)(2)(2)Epstein-BarrEpstein-BarrEpstein-BarrEpstein-Barrvirusvirusvirusvirus:nasopharyngeal:nasopharyngeal:nasopharyngea
19、l:nasopharyngealcarcinomacarcinomacarcinomacarcinoma(3)HBV:hepatocytecarcinoma(3)HBV:hepatocytecarcinoma(3)HBV:hepatocytecarcinoma(3)HBV:hepatocytecarcinoma3.Helicobacterpylori:chronicgastritis,3.Helicobacterpylori:chronicgastritis,3.Helicobacterpylori:chronicgastritis,3.Helicobacterpylori:chronicga
20、stritis, BBBBlymphomaofstomachlymphomaofstomachlymphomaofstomachlymphomaofstomach8.3 Internal factors and its mechanism8.3.18.3.1 InheritedInherited predispositionpredisposition totocarcinogenscarcinogens1.1.1.1. InheritedInheritedInheritedInherited cancercancercancercancer syndromesyndromesyndromes
21、yndrome (Autosomal(Autosomal(Autosomal(Autosomaldominantdominantdominantdominant)FamilialretinoblastomaFamilialretinoblastoma2.Autosomalrecessivesyndromes:2.Autosomalrecessivesyndromes:Bloomsyndrome,fanconianemiaBloomsyndrome,fanconianemia3.Familialcancer:breast,ovary,colon3.Familialcancer:breast,ov
22、ary,colon8.3.2 Tumor immunity1.Tumorantigen:1.Tumorantigen:1.Tumorantigen:1.Tumorantigen: TumorTumorTumorTumorspecificspecificspecificspecificAgAgAgAg:only:only:only:onlyininininneoplasticneoplasticneoplasticneoplasticTumorassociatedAg:CEA,AFPTumorassociatedAg:CEA,AFPTumorassociatedAg:CEA,AFPTumoras
23、sociatedAg:CEA,AFP2.Antitumorimmunity:mainlycellimmunity2.Antitumorimmunity:mainlycellimmunity2.Antitumorimmunity:mainlycellimmunity2.Antitumorimmunity:mainlycellimmunityTcell:lymphotoxinTcell:lymphotoxinTcell:lymphotoxinTcell:lymphotoxinNKcell,Macrophage:ADCCNKcell,Macrophage:ADCCNKcell,Macrophage:
24、ADCCNKcell,Macrophage:ADCC3.Immunesurveilance:3.Immunesurveilance:3.Immunesurveilance:3.Immunesurveilance: ImmunodificientImmunodificientImmunodificientImmunodificienthost/host/host/host/immunosuppressedimmunosuppressedimmunosuppressedimmunosuppressed4.Immunotherapy:stimulatetheendogenous4.Immunothe
25、rapy:stimulatetheendogenous4.Immunotherapy:stimulatetheendogenous4.Immunotherapy:stimulatetheendogenous reaction,reaction,reaction,reaction, increaseincreaseincreaseincrease thethethethe functionfunctionfunctionfunction ofofofofantitumorantitumorantitumorantitumorn n复复复复习习思考思考思考思考题题n n1.1.1.1.比比比比较较
26、良、良、良、良、恶恶性性性性肿肿瘤的区瘤的区瘤的区瘤的区别别？n n2.2.2.2.高分化高分化高分化高分化鳞鳞癌的癌的癌的癌的结结构特点？构特点？构特点？构特点？n n3.3.3.3.何何何何谓实谓实性癌？性癌？性癌？性癌？简简述其病理特点？述其病理特点？述其病理特点？述其病理特点？n n4.4.4.4.异型性、分化程度及与异型性、分化程度及与异型性、分化程度及与异型性、分化程度及与肿肿瘤良瘤良瘤良瘤良恶恶性的关系？性的关系？性的关系？性的关系？n n5.5.5.5.肿肿瘤性增生与炎症性增生的区瘤性增生与炎症性增生的区瘤性增生与炎症性增生的区瘤性增生与炎症性增生的区别别？n n6.6.6.6
27、.恶恶性性性性肿肿瘤瘤瘤瘤对对机体的影响？机体的影响？机体的影响？机体的影响？n n7.7.7.7.何何何何谓谓癌癌癌癌前前前前病病病病变变，请请列列列列举举5 5 5 5种种种种癌癌癌癌前前前前病病病病变变或或或或癌癌癌癌前前前前疾疾疾疾病病病病，并并并并说说明明明明应应如何正确如何正确如何正确如何正确对对待癌前病待癌前病待癌前病待癌前病变变。n n8.8.8.8.腺腺腺腺上上上上皮皮皮皮可可可可形形形形成成成成哪哪哪哪几几几几种种种种类类型型型型的的的的恶恶性性性性肿肿瘤瘤瘤瘤，并并并并简简述述述述各各各各自自自自的形的形的形的形态态特点？特点？特点？特点？n n9.9.9.9.试试述述述述转转移瘤的形成移瘤的形成移瘤的形成移瘤的形成过过程及其形程及其形程及其形程及其形态态特点？特点？特点？特点？n n10.10.10.10.举举例例例例说说明明明明为为什么什么什么什么说说良良良良恶恶性性性性肿肿瘤的区瘤的区瘤的区瘤的区别别是相是相是相是相对对的？的？的？的？
