医科大学病理学英文课件Section8.Etiologyandpathogenesisoftumor

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 oncogenesis8.1.1 Oncogene1. Protooncogene , oncogene and products(1) Protooncogene: ce

4、llular 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 Gene lification promoter insertion(4) P

5、roducts and functions of protooncogenesGrowth factors: PDGF,FGF, EGFGrowth factor receptorsSignal- transducing proteins: rasNuclear regulatory proteins: mycCell cycle regulatory proteins: cyclins8.1.2 Tumor suppressor gene1.Concept: cellular genes that exist in normal cells inhibit normal growth and

6、 cause cells to malignant transform when they become inactive.2. Exles: Rb , p53 , P16,TGF-, BRCA-1 , BRCA-23. mechanism: allele mutation, deletion, methylation8.1.3 Genes that regulate apoptosis and DNA repair Genes that regulate apoptosis Bcl (B-cell lymphoma)family: Bcl-2: inhibit apoptosis Bax:

7、induce apoptosis2. Genes that regulate DNA repair: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 tu

8、mor8.1.5 Molecular basis of multistep carcinogenesis MORPHOLOGICAPPEARANCEMOLECULARCHANGENormal epitheliumHyperproliferative epitheliumEarly adenomaIntermediate adenomaLate adenomaCarcinomaLoss or mutation of APC locus on chromosome 5qLoss of DNA methylationMutation of ras geneon chromosome 12pLoss

9、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 61:759,1990.Copyright 1990,Cell Press.)8.2

10、Environmental factors and their mechanism 8.2.1 Cheminal carcinogenic agentsIndirect-acting agentPolycyclic hydrocarbons:in fossil fuel or combustion of tabacco in smoking ,relate to thedevelopment of skin, lung, stomach carcinoma(2) Aromatic amines and azo dyes: bladder, hepatocellular carcinoma(3)

11、 Aflatoxin: potent hepatocarcinogen(4)Nitrosamines: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

12、factors1. Ionizing radiation: X-ray, -ray related to leukemia , carcinoma of skin, lung, breast,colon.2. UV: skin carcinoma3. Others: asbestos mesothelioma artificial mammary carcinoma8.2.3 Biologic carcigenic agents1. RNA virus: Transduction/ insertional mutagenesis HTLV-1 : human T cell leukemia/

13、lymphoma2. DNA virus:(1) HPV:cervical squamous cell carcinoma(2) Epstein-Barr virus :nasopharyngeal carcinoma(3) HBV: hepatocyte carcinoma3. Helicobacter pylori: chronic gastritis, B lymphoma of stomach8.3 Internal factors and its mechanism8.3.1 Inherited predisposition to carcinogens1. Inherited ca

14、ncer syndrome (Autosomal dominant) Familial retinoblastoma2. Autosomal recessive syndromes: Bloom syndrome, fanconi anemia3. Familial cancer: breast,ovary,colon8.3.2 Tumor immunity1.Tumor antigen: Tumor specific Ag :only in neoplastic Tumor associated Ag: CEA, AFP2. Antitumor immunity: mainly cell immunity T cell: lymphotoxin NK cell, Macrophage :ADCC3. Immunesurveilance: Immunodificient host/ immunosuppressed4. Immunotherapy: stimulate the endogenous reaction, increase the fu