Presentation on theme: "Etiology and Oncogenesis of Tumors"— Presentation transcript:
1 Etiology and Oncogenesis of Tumors Section 12Etiology and Oncogenesis of Tumors
2 Additional mutations (progression) Normal cellAcquired (environmental) DNA damaging agents:ChemicalsRadiationvirusesSuccessful DNA repairDNA DamageFailure of DNA repairInherited mutations in: Genes affecting DNA repairMutations in the genome of somatic cellsActivation of growth- promoting oncogenesAlterations of genes that regulate apoptosisInactivation of cancer suppressor genesExpression of altered gene products and loss of regulatory gene productsClonal expansionAdditional mutations (progression)HeterogeneityQuoted from Robbins《 Pathology Basis of disease》Malignant neoplasm
3 1. Molecular Basis of Tumor Nonlethal genetic damage lies at the core of carcinogenesisFour classes of regulatory genes, protooncogene, cancer suppressor gene, regulated apoptosis gene, and DNA repair gene, are the principal targets of genetic damage.Carcinogenesis is a multistep process at both the phenotypic and genetic levels.
4 (1) Oncogenes and cancer ① Protein products of oncogenesa. Growth factorsb. Growth factors receptorsc. Signal transducing proteinsd. Nuclear transcription proteinse. Cyclones and cyclic-dependent kinases
5 ② Activation of oncogenes a. Point mutationsb. Chromosome rearrangementsTranslocationsInversionsC. amplification
6 (Quoted from Robbins《 Pathology Basis of disease》)
7 (Quoted from Robbins《 Pathology Basis of disease》)
9 Table Selected oncogenes their mode of activation and associated human tumors CategoryProtooncogeneMechanismAssociatedHuman TumorGrowth FactorsPDGF-β chainFibroblast growth factors SisHst-1Int-2OverexpressionAmplificationAstrocytomaOsteosarcomaStomach cancerBladder cancerBreast cancerMelanoma
10 ras Category Protooncogene Mechanism Associated Human Tumor Growth factor ReceptorsEGF-receptor familyCSF-1 receptorErb-B1erb-B2erb-B3fmsret*OverexpressionAmplificationPoint mutationRearrangementSquamous cell carcinomas of lungBreast, ovarian, lung, and stomach cancersBreast cancersLeukemiaMultiple endocrine neoplasia 2A and B. Familial medullary thyroid carcinomaSporadic papillary carcinomas of thyroidProteins involved in signal transductionGTP-bindingrasPoint mutationsA variey of human cancers, including lung, colon, pancreas; many leukemias
14 (2) Cancer suppressor genes ① Molecules that regulated nuclear transcription and cell cycleRb gene: 13q14, G × SP53 gene: 17p13.1, related to 50% of human tumorsBRCA- l gene: 17q12-21,BRCA-2 gene: 13q12-13
15 ② Molecules that regulated signal transduction NF-1 gene: 17q11.2APC gene: 5q21
16 ③ Cell surface receptors SMAD2 gene:SMAD4 gene:DCC gene: 18q21
18 (Quoted from Robbins《 Pathology Basis of disease》)
19 Selected tumor- suppressor genes involved in human neoplasms Subcellular locationGeneFunctionTumors associated with somatic mutationsTumors associated with inherited mutationsCell surfaceTGF-β receptorE-cadherinGrowth inhibitionCell adhesionCarcinomas of colonCarcinoma of stomach, breastUnknownFamilial gastric cancerUnder plasma membraneNF- 1Inhibition of ras signal transductionSchwannomasNeurofibromatosis type Ⅰ and sarcomasCytoskeletonNF- 2Schwannomas and meningiomasNeurofibromatosis type Ⅱ; acoustic schwannomas and meningiomas
20 Subcellular location Gene FunctionTumors associated with somatic mutationsTumors associated with inherited mutationsCttisikAPCInhibition of signal transductionCarcinomas of stomach, colon, pancreas; melanomaFamilial adenomatous polyposis coli; colon cancerNucleusRbRegulation of cell cycleRetinoblastoma; osteosarcoma; carcinomas of breast, colon, lungRetinoblastomas, osteosaromaP53Regulation of cell cycle and apoptosis in response to DNA damageMost human cancersLi- Fraumeni syndrome; multiple carcinomas and sarcomas
21 Subcellular location Gene FunctionTumors associated with somatic mutationsTumors associated with inherited mutationsWT-1Nuclear transcriptionWukns tynirWilms tumorP16 (INK4a)Regulation of cell cycle by inhibiting cyclindependent kinasesPancreatic, esophageal cancersMalignant melanomaBRCA- 1DNA repairCarcinomas of female breast and ovaryBRCA-2Carcinomas of male and female breast
23 (Quoted from Robbins《 Pathology Basis of disease》)
24 (4) Genes that regulate DNA repair Humans literally swim in a sea of environmental carcinogens. Although exposure to naturally occurring DNA- damaging agents, such as ionizing radiation, sunlight, and dietary carcinogens, is common, cancer is a relatively rare outcome of such encounters.
25 This happy state of affairs results from the ability of normal cells to repair DNA damages and thus prevent mutations in genes that regulate cell growth and apoptosis. In addition to possible DNA damage from environmental agents, the DNA of normal dividing cells is also susceptible to alterations resulting from errors that occur spontaneously during DNA replication. Such mistakes, if not repaired promptly, can also push the cells along the slippery sloe of neoplastic transformation.
26 The importance of DNA repair in maintaining the integrity of the genome is highlighted by several inherited disorders in which genes that encode proteins involved in DNA repair are defective. Those born with such inherited mutations of DNA repair proteins are at a greatly increased risk of developing cancer. Several examples are discussed next.
27 (5) Telomere and tumor telomerase activity increased in majority of human tumors.
28 (Quoted from Robbins《 Pathology Basis of disease》)
29 (6) Molecular Basis of Multistep Carcinogenesis
30 2. Carcinogenic agentsA large number of agents cause genetic damage and inchece neoplastic transformation of cells(1) Chemical carcinogensChemical carcinogenesis is also a multistep process.
31 ① Inition of carcinogensis Chemical carcinogens are diverse in structure, but they fall into one of two categories:a. Direct-acting chemical carcinogenesb. Indirect-acting chemical carcinogens (procarcinogenes),Which require metabolic conversion in vivo to produce.Ultimate carcinogens capable of transforming cells.
32 Both of them are highly reactive electrophiles that can react with nucleophilic (electron-rich) sites in the cells.These reactions are nonenzymatic and result in the formation of covalent adducts between the chemical carcinogen and nucleotide in DNA.
33 The carcinogenic potency of a chemical is determined not only by the inherent reactivity of its electrophilic derivative, but also by the balance between metabolic activation and inactivation reactions.If initiation occurs, carcinogen-altered cells could be heritable.
34 ② Promotion of carcinogenesis Promoters earn induce tumors in initiated cells, but they are nontumorigenic by them selves.Prompters render cells susceptible to additional mutations by causing cellular proliferation.
35 Altered differentiation CARCINOGENMetabolic activationExcretiElectrophilicintermediatesINITIATIONDNArepairNormal cellBinding to DNA:Adduct formationCell deathPermanent DNA lesion:Initiated cellCell proliferaion:Altered differentiationPROMOTIONPRENEOPLASTIC CLONEAdditionalmutationsProliferationMALIGNANT NEOPLASM(Quoted from Robbins《 Pathology Basis of disease》)
36 Major Chemical carcinogens ① Direct acing alkylating agents(烷化剂)a. In general they are weak carcinogens.But they are important because many of them are anticancer drugs.b. e. g. Cyclophosphamide(环磷酰胺), Chlorambucil, busulfan, melphalan.c. Induce: lymphoid neoplasms, leukemia
37 ② Polycyclic aromatic hydrocarbons (多环芳烃) a. The most potent carcinogens.b. Require metabolic activationc. Can induce tumors in a wide variety oftissues and species.
38 ③ Aromatic amines(芳族胺) and azo dyes a. Mainly in liverb. Can induce hepatocellular carcinomas and bladder cancer
39 ④ Naturally occurring carcinogens Aflatixi(黄曲霉毒素)B1 and HBV related to hepatocellular carcinoma⑤ Nitrosamine(亚硝胺) and amidesRelated to gastric carcinoma
40 ⑥ Miscellaneous agents a. Asbestos associated with increased incidence of bronchogenic carcinomas, mesotheliomas, gastrointestinal cancersb. Chromium, nickel, and other metals, when volatilized and inhaled, have caused lung cancerc. Arsenic associated with skin cancer
41 ⑦ Promoters of chemical carcinogenesis a. Hormones: e. g. estrogens as promotes of liver tamers, postmenopausal endometrial carcinomab. Bile salts: high levels of dietary fat associated with increased risk of colon cancer that may be related to more bile acids.
42 (2) Radiation carcinogenesis ① UV light is clearly implicated in causation of skin cancers; Ionizing radiations, atomic bomb have produced a variety of forms of malignant neoplastic, especially in leukemia lymphoma, thyroid cancers② Radiation may inhibited cell division, inactive enzymes, induce mutations.
43 (3) Viral carcinogens ① RNA oncogenic viruses a. Acute transforming virusesWhich containing viral oncogene (src, abl, myb) may directly trans form human oncogenesb. Slow transforming virusesWhich not containing viral oncogene may insert the sites that nearby human oncogene and make them overdressed now only human fell leukemia virus type 1 (HTLV-1) is firmly implicated in the causation of human caner
44 ② DNA oncogenic viruses Transforming DNA viruses form stable association with the host cell genome and are important for cell transformation.
45 a. Human papillomavirus (HPV) HPV-1, 2, 4, 7 can cause benign squamous papillomas in human;HPV-16, 18 are found in approximately 85% of severe squamous dysplasias, carcinoma in situ, and invasine squamous cell can cars.E6, E7 proteins of HPV-16, 18E6 protein can degrade the P53 gene product ;E7 protein may bind to the underphosphorylated form of the tumor- suppressor protein PRb.
46 b. Epstein-Barr virus (EBV) EBV has been implicated in pathogenesis of four humanTumors: Burkitt lymphoma, B-cell lymphoma, Hodgken disease and nasopharyngeal carcinoma.c. Hepatitis β virus (HBV)Epidemiologic studies strongly suggest a close association between HBV infection and the occurrence of liver cancer.
47 3. Influence factors of oncogenesis and development (1) Heredity factors① Autosomal dominant inherited cancer syndromesFamilial retinoblastomaFamilial adenomatous polyps of the colonMultiple endocrine neoplasia syndromesNeurofibromatosis types 1 and 2Von Hipped- Lindace syndrome(cerebellar hemengioblastomas, retinal angiomas, epididymal tumors)
48 ② Familial cancers Breast cancer, ovarian cancer Colon cancer other than familial adenomatous polypsThey are associated with specific marker phenotype.Some of them may be linked to the inheritance of mutant genes.
49 ③ Autosomal recessive syndromes of defective DNA repair gene xeroderma pigmentosum: 着色性干皮病 易发基底细胞癌,鳞状细胞癌,黑色素溜Ataxia-telangiectasia:毛细管扩张共济失调,易发白血病,淋巴瘤Bloom syndrome:先天性脸部血管扩张性红斑,身材矮小发育不良。隐性遗传,异常基因位於 15q 易发白血病,恶性肿瘤Fanconi anemia:一种罕见的常染色体隐性遗传性血液系统疾病，属于先天性再障
50 (2) Host defense against tumors- Tumor immunity ① Tumor antigena. Tumor- specific antigen (TSA)b. Tumor- associated antigen (TAA)
51 Embryonic antigens: e. g. AFP, CEA Differentiation antigens: CD10Tissue-specific antigens: e. g. tyrosinaseAntigens resulting from mutations: e. g. mutatead P53, K-ras, CDK4Overexpressed antigens: e. g, c-erbB2 proteinViral antigens: e. g. E7
52 ② Antitumor effector mechanisms Both cell-mediated and humoral immunity can have antitumor activity.a. Major immune antitumor cells:Cytotoxic T lymphocytesNatural killer cellsMacrophages
53 b. ImmunosurveillanceThe tumor cells have developed mechanisms to escape from the immune system in hosts.Selective outgrowth of antigen-negative variantsLoss or reduced expression of histocompatibility antigensLack of costimulationImmunosuppressionApoptosis of cytotoxic T cells.
54 (3) The Others① Endocrine② Sex③ Age④ Ethnic⑤ Geography