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Etiology and Oncogenesis of Tumors

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1 Etiology and Oncogenesis of Tumors
Section 12 Etiology and Oncogenesis of Tumors

2 Additional mutations (progression)
Normal cell Acquired (environmental) DNA damaging agents: Chemicals Radiation viruses Successful DNA repair DNA Damage Failure of DNA repair Inherited mutations in: Genes affecting DNA repair Mutations in the genome of somatic cells Activation of growth- promoting 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 Quoted from Robbins《 Pathology Basis of disease》 Malignant neoplasm

3 1. Molecular Basis of Tumor
Nonlethal genetic damage lies at the core of carcinogenesis Four 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 oncogenes a. Growth factors b. Growth factors receptors c. Signal transducing proteins d. Nuclear transcription proteins e. Cyclones and cyclic-dependent kinases

5 ② Activation of oncogenes
a. Point mutations b. Chromosome rearrangements Translocations Inversions C. amplification

6 (Quoted from Robbins《 Pathology Basis of disease》)

7 (Quoted from Robbins《 Pathology Basis of disease》)

8 (quoted from Robbins Basic Pathology, 2003)

9 Table Selected oncogenes their mode of activation and associated human tumors
Category Protooncogene Mechanism Associated Human Tumor Growth Factors PDGF-β chain Fibroblast growth factors  Sis Hst-1 Int-2 Overexpression Amplification Astrocytoma Osteosarcoma Stomach cancer Bladder cancer Breast cancer Melanoma

10 ras Category Protooncogene Mechanism Associated Human Tumor
Growth factor Receptors EGF-receptor family CSF-1 receptor Erb-B1 erb-B2 erb-B3 fms ret* Overexpression Amplification Point mutation Rearrangement Squamous cell carcinomas of lung Breast, ovarian, lung, and stomach cancers Breast cancers Leukemia Multiple endocrine neoplasia 2A and B. Familial medullary thyroid carcinoma Sporadic papillary carcinomas of thyroid Proteins involved in signal transduction GTP-binding ras Point mutations A variey of human cancers, including lung, colon, pancreas; many leukemias

11 Nonreceptor tyrosine kinase abl Translocation
Category Protooncogene Mechanism Associated Human Tumor Nonreceptor tyrosine kinase abl Translocation Chronic myeloid leukemia Acute lymphoblastic leukemia Nuclear regulatory proteins Transcriptional activators Myc N-myc L-myc Amplification Burkitt lymphoma Neuroblastoma Small cell carcinoma of lung

12 Category Protooncogene Mechanism Associated Human Tumor Cell cycle regulators Cyclins Cyclin-dependent kinase Cyclin D CDK4 Translocation Amplification Amplification or point mutation Mantle cell lymphoma Breast, liver, esophageal cancers Glioblastoma, melanoma, sarcoma PDGF, platelet-derived growth factor; EGF, epidermal growth factor; CSF, colony-stimulating factor; GTP, guanosine triphosphate. * ret protooncogene is a receptor for glial cell line-derived neurotrophic factor.

13 几种常见的癌基因及其激活方式和相关的人类肿瘤 编码的蛋白质 原癌基因 激活机制 相关人类肿瘤 生长因子:
编码的蛋白质 原癌基因 激活机制 相关人类肿瘤 生长因子: PDGF-β链 sis 过度表达 星形细胞瘤、骨肉瘤 FGF HST 过度表达 胃癌 INT 扩增   膀胱癌、乳腺癌、黑色素瘤 TGF-α TGF-α 过度表达 星形细胞瘤、肝细胞癌 HGF HGF 过度表达 甲状腺癌 生长因子受体: EGF受体家族 erb-B1(ECFR) 过度表达 肺鳞癌、神经胶质瘤 erb-B 扩增 乳腺癌、卵巢癌 CSF-1受体 FMS 点突变 白血病 神经营养因子受体 RET 点突变 多发性内分泌瘤病2A和B, 家族性甲状腺髓样癌 PDGF受体 PDGF-R 过度表达 神经胶质瘤 干细胞因子受体 KIT 点突变 胃肠间质细胞瘤、其它软组织肿瘤 信号转导蛋白: GTP结合蛋白 K-RAS 点突变 结肠、肺、胰腺肿瘤 H-RAS 点突变 膀胱与肾肿瘤 N-RAS 点突变 黑色素瘤、多种造血系统恶性肿瘤 非受体酪氨酸激酶 ABL 易位 慢性髓性白血病、急性淋巴母细胞性白血病 RAS信号转导 BRAF 点突变 黑色素瘤 WNT信号转导 β-catenin 点突变 过度表达 肝母细胞瘤、肝细胞癌 核调节蛋白: 转录激活蛋白 C-MYC 易位 伯基特淋巴瘤 N-MYC 扩增   神经母细胞瘤、小细胞肺癌 L-MYC 扩增 小细胞肺癌 细胞周期调节素: 细胞周期素 Cyclin D 易位 套细胞淋巴瘤 扩增 乳腺癌、食管癌 Cyclin E 过度表达 乳腺癌 周期素依赖激酶 CDK 扩增或点突变 胶质母细胞瘤、黑色素瘤、肉瘤 (引自Robbin Pathologic Basis of Disease,2005)

14 (2) Cancer suppressor genes
① Molecules that regulated nuclear transcription and cell cycle Rb gene: 13q14, G × S P53 gene: 17p13.1, related to 50% of human tumors BRCA- l gene: 17q12-21, BRCA-2 gene: 13q12-13

15 ② Molecules that regulated signal transduction
NF-1 gene: 17q11.2 APC gene: 5q21

16 ③ Cell surface receptors
SMAD2 gene: SMAD4 gene: DCC gene: 18q21

17 ④ Other tumor suppressor genes
NF- 2 gene VHL gene: 3p PTEN gene: 10q23, WT- 1 gene: 11p13

18 (Quoted from Robbins《 Pathology Basis of disease》)

19 Selected tumor- suppressor genes involved in human neoplasms
Subcellular location Gene Function Tumors associated with somatic mutations Tumors associated with inherited mutations Cell surface TGF-β receptor E-cadherin Growth inhibition Cell adhesion Carcinomas of colon Carcinoma of stomach, breast Unknown Familial gastric cancer Under plasma membrane NF- 1 Inhibition of ras signal transduction Schwannomas Neurofibromatosis type Ⅰ and sarcomas Cytoskeleton NF- 2 Schwannomas and meningiomas Neurofibromatosis type Ⅱ; acoustic schwannomas and meningiomas

20 Subcellular location Gene
Function Tumors associated with somatic mutations Tumors associated with inherited mutations Cttisik APC Inhibition of signal transduction Carcinomas of stomach, colon, pancreas; melanoma Familial adenomatous polyposis coli; colon cancer Nucleus Rb Regulation of cell cycle Retinoblastoma; osteosarcoma; carcinomas of breast, colon, lung Retinoblastomas, osteosaroma P53 Regulation of cell cycle and apoptosis in response to DNA damage Most human cancers Li- Fraumeni syndrome; multiple carcinomas and sarcomas

21 Subcellular location Gene
Function Tumors associated with somatic mutations Tumors associated with inherited mutations WT-1 Nuclear transcription Wukns tynir Wilms tumor P16 (INK4a) Regulation of cell cycle by inhibiting cyclindependent kinases Pancreatic, esophageal cancers Malignant melanoma BRCA- 1 DNA repair Carcinomas of female breast and ovary BRCA-2 Carcinomas of male and female breast

22 (3) Genes that regulate apoptosis
Inhibit apoptosis: bc1- 2 gene (18q21), bc1-Xl Favor apoptosis: bax, bad, bc1-xS

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 agents A large number of agents cause genetic damage and inchece neoplastic transformation of cells (1) Chemical carcinogens Chemical 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 carcinogenes b. 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
CARCINOGEN Metabolic activation Excreti Electrophilic intermediates INITIATION DNA repair Normal cell Binding to DNA: Adduct formation Cell death Permanent DNA lesion: Initiated cell Cell proliferaion: Altered differentiation PROMOTION PRENEOPLASTIC CLONE Additional mutations Proliferation MALIGNANT 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 activation c. Can induce tumors in a wide variety of tissues and species.

38 ③ Aromatic amines(芳族胺) and azo dyes
a. Mainly in liver b. Can induce hepatocellular carcinomas and bladder cancer

39 ④ Naturally occurring carcinogens
Aflatixi(黄曲霉毒素)B1 and HBV related to hepatocellular carcinoma ⑤ Nitrosamine(亚硝胺) and amides Related to gastric carcinoma

40 ⑥ Miscellaneous agents
a. Asbestos associated with increased incidence of bronchogenic carcinomas, mesotheliomas, gastrointestinal cancers b. Chromium, nickel, and other metals, when volatilized and inhaled, have caused lung cancer c. Arsenic associated with skin cancer

41 ⑦ Promoters of chemical carcinogenesis
a. Hormones: e. g. estrogens as promotes of liver tamers, postmenopausal endometrial carcinoma b. 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 cancers ② Radiation may inhibited cell division, inactive enzymes, induce mutations.

43 (3) Viral carcinogens ① RNA oncogenic viruses
a. Acute transforming viruses Which containing viral oncogene (src, abl, myb) may directly trans form human oncogenes b. Slow transforming viruses Which 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, 18 E6 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 human Tumors: 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 factors ① Autosomal dominant inherited cancer syndromes Familial retinoblastoma Familial adenomatous polyps of the colon Multiple endocrine neoplasia syndromes Neurofibromatosis types 1 and 2 Von Hipped- Lindace syndrome(cerebellar hemengioblastomas, retinal angiomas, epididymal tumors)

48 ② Familial cancers Breast cancer, ovarian cancer
Colon cancer other than familial adenomatous polyps They 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 antigen a. Tumor- specific antigen (TSA) b. Tumor- associated antigen (TAA)

51 Embryonic antigens: e. g. AFP, CEA
Differentiation antigens: CD10 Tissue-specific antigens: e. g. tyrosinase Antigens resulting from mutations: e. g. mutatead P53, K-ras, CDK4 Overexpressed antigens: e. g, c-erbB2 protein Viral 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 lymphocytes Natural killer cells Macrophages

53 b. Immunosurveillance The tumor cells have developed mechanisms to escape from the immune system in hosts. Selective outgrowth of antigen-negative variants Loss or reduced expression of histocompatibility antigens Lack of costimulation Immunosuppression Apoptosis of cytotoxic T cells.

54 (3) The Others ① Endocrine ② Sex ③ Age ④ Ethnic ⑤ Geography

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