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1、中国医科大学病理学英文课件8 Still waters run deep.流静水深流静水深,人静心深人静心深 Where there is life,there is hope。有生命必有希望。有生命必有希望Acquired(environmental)DNA damaging agents chemicals radiation virusesNORMAL CELLDNA DamageSuccessfulDNA repairMutations in the Genome of Somatic cellsFailure of DNA repair Activation of growth-pr
2、omoting oncogenes Alterations of genes that regulate 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
3、 DNA repair Genes affecting cell growth or apoptosis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 oncogenesis8.1.1 Oncogene1.Protooncog
4、ene,oncogene and products(1)Protooncogene:cellular genes that promote normal cell growth and differentiation,exist in normal cells,in the form of inactivity.(2)Oncogene:derived from protooncogene promote abnormal growth.(3)Mode of protooncogenes activation Point mutation Chromosomal rearrangement Ge
5、ne amplification promoter insertion(4)Products and functions of protooncogenesGrowth factors:PDGF,FGF,EGFGrowth factors:PDGF,FGF,EGFGrowth factor receptorsGrowth factor receptorsSignal-transducing proteins:rasSignal-transducing proteins:rasNuclear regulatory proteins:mycNuclear regulatory proteins:m
6、ycCell cycle regulatory proteins:cyclinsCell cycle regulatory proteins:cyclins8.1.2 Tumor suppressor gene1.Concept:cellular genes that exist in normal cells inhibit normal growth and cause cells to malignant transform when they become inactive.2.Examples:Rb,p53,P16,TGF-,Rb,p53,P16,TGF-,BRCA-1,BRCA-2
7、 BRCA-1,BRCA-23.mechanism:allele mutation,3.mechanism:allele mutation,deletion,methylation deletion,methylation8.1.3 Genes that regulate apoptosis and DNA repair 1.Genes that regulate apoptosis 2.Bcl(B-cell lymphoma)family:3.Bcl-2:inhibit apoptosis4.Bax:induce apoptosis5.2.Genes that regulate DNA re
8、pair:8.1.4 Telomeres,telomerase and cancer1.Telomeres shorting is believed to be a clock that counts cell division,is a tumor-suppressive mechanism.2.Telomerase:Sustain the function of telomeres Absent from most somatic cell Increased activity of it tumor8.1.5 Molecular basis of multistep carcinogen
9、esis MORPHOLOGICAPPEARANCEMOLECULARCHANGENormal epitheliumHyperproliferative epitheliumEarly adenomaIntermediate adenomaLate adenomaCarcinomaLoss or mutation of APC locus on chromosome 5qLoss of DNA methylationMutation of ras geneon chromosome 12pLoss of tumor suppressoron chromosome 18qLoss of p53
10、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 61:759,1990.Copyright 1990,Cell Press.)8.2 Environmental factors and their mechanism 8.2.1
11、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 azo dyes:bladder,hepatocellular carcinoma(3)Aflatoxin:potent hepatocarcinogen(4)Nitrosam
12、ines:lung,gastric,esophagus,2.Direct-acting agents(1)Alkylatingand acylating agents:anticancer drugs cyclophosphamide(2)Others arsenicskin carcinoma chromiumlung carcinoma cadmiumprostate carcinoma nickellung carcinoma 8.2.2 Physical carcinogenic factors1.Ionizing radiation:X-ray,-ray related to leu
13、kemia,carcinoma of skin,lung,breast,colon.2.UV:skin carcinoma3.Others:asbestos mesothelioma artificial mammary carcinoma8.2.3 Biologic carcigenic agents1.1.RNA virus:RNA virus:Transduction/insertional mutagenesis Transduction/insertional mutagenesis HTLV-1:human T cell leukemia/lymphoma HTLV-1:human
14、 T cell leukemia/lymphoma2.2.DNA virus:DNA virus:(1)HPV:cervical squamous cell carcinoma(1)HPV:cervical squamous cell carcinoma(2)Epstein-Barr virus:nasopharyngeal carcinoma(2)Epstein-Barr virus:nasopharyngeal carcinoma(3)HBV:hepatocyte carcinoma(3)HBV:hepatocyte carcinoma3.3.Helicobacter pylori:Hel
15、icobacter pylori:chronic gastritis,chronic gastritis,B lymphoma of stomach B lymphoma of stomach8.3 Internal factors and its mechanism8.3.1 Inherited predisposition to carcinogens1.Inherited cancer syndrome(Autosomal dominant1.Inherited cancer syndrome(Autosomal dominant)Familial retinoblastoma2.Aut
16、osomal recessive syndromes:Bloom syndrome,fanconi anemia3.Familial cancer:breast,ovary,colon8.3.2 Tumor immunity1.Tumor antigen:1.Tumor antigen:Tumor specific Ag:only in neoplastic Tumor specific Ag:only in neoplastic Tumor associated Ag:CEA,AFP Tumor associated Ag:CEA,AFP2.Antitumor immunity:mainly
17、 cell immunity2.Antitumor immunity:mainly cell immunity T cell:lymphotoxin T cell:lymphotoxin NK cell,Macrophage:ADCC NK cell,Macrophage:ADCC3.Immunesurveilance:3.Immunesurveilance:Immunodificient host/immunosuppressed Immunodificient host/immunosuppressed4.Immunotherapy:stimulate the endogenous 4.I
18、mmunotherapy:stimulate the endogenous reaction,increase the function of antitumor reaction,increase the function of antitumorn n复习思考题复习思考题复习思考题复习思考题n n1.1.比较良、恶性肿瘤的区别？比较良、恶性肿瘤的区别？比较良、恶性肿瘤的区别？比较良、恶性肿瘤的区别？n n2.2.高分化鳞癌的结构特点？高分化鳞癌的结构特点？高分化鳞癌的结构特点？高分化鳞癌的结构特点？n n3.3.何谓实性癌？简述其病理特点？何谓实性癌？简述其病理特点？何谓实性癌？简述其病理
19、特点？何谓实性癌？简述其病理特点？n n4.4.异型性、分化程度及与肿瘤良恶性的关系？异型性、分化程度及与肿瘤良恶性的关系？异型性、分化程度及与肿瘤良恶性的关系？异型性、分化程度及与肿瘤良恶性的关系？n n5.5.肿瘤性增生与炎症性增生的区别？肿瘤性增生与炎症性增生的区别？肿瘤性增生与炎症性增生的区别？肿瘤性增生与炎症性增生的区别？n n6.6.恶性肿瘤对机体的影响？恶性肿瘤对机体的影响？恶性肿瘤对机体的影响？恶性肿瘤对机体的影响？n n7.7.何何何何谓谓谓谓癌癌癌癌前前前前病病病病变变变变，请请请请列列列列举举举举5 5种种种种癌癌癌癌前前前前病病病病变变变变或或或或癌癌癌癌前前前前疾疾疾
20、疾病病病病，并并并并说明应如何正确对待癌前病变。说明应如何正确对待癌前病变。说明应如何正确对待癌前病变。说明应如何正确对待癌前病变。n n8.8.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类类型型型型的的的的恶恶恶恶性性性性肿肿肿肿瘤瘤瘤瘤，并并并并简简简简述述述述各各各各自自自自的的的的形态特点？形态特点？形态特点？形态特点？n n9.9.试述转移瘤的形成过程及其形态特点？试述转移瘤的形成过程及其形态特点？试述转移瘤的形成过程及其形态特点？试述转移瘤的形成过程及其形态特点？n n10.10.举例说明为什么说良恶性肿瘤的区别是相对的？举例说明为什么说良恶性肿瘤的区别是相对的？举例说明为什么说良恶性肿瘤的区别是相对的？举例说明为什么说良恶性肿瘤的区别是相对的？