6.5Etiology&Oncogenesis

Section 12 Etiology and Oncogenesis of

Tumors

Acquired (environmental) DNA damaging agents:ChemicalsRadiationviruses

Normal cell

DNA Damage

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

Malignant neoplasm

Successful DNA repair

Failure of DNA repair Inherited mutations in: Genes affecting DNA repair

Clonal expansion

Additional mutations (progression)

HeterogeneityQuoted from Robbins 《 Pathology Basis of disease 》

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.

(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

② Activation of oncogenes

a. Point mutations

b. Chromosome rearrangements Translocations Inversions C. amplification

(Quoted from Robbins 《 Pathology Basis of disease 》 )

（ quoted from Robbins Basic Pathology, 2003 ）

Table Selected oncogenes their mode of activation and associated

human tumors

Category Protooncogene

Mechanism AssociatedHuman Tumor

Growth Factors

PDGF-β chain Fibroblast growth factors

Sis

Hst-1Int-2

Overexpression

OverexpressionAmplification

Astrocytoma Osteosarcoma Stomach cancerBladder cancerBreast cancerMelanoma



Growth factor ReceptorsEGF-receptor family

CSF-1 receptor

Erb-B1erb-B2erb-B3

fmsret*

OverexpressionAmplificationOverexpressionPoint mutationPoint mutation

Rearrangement

Squamous cell carcinomas of lungBreast, ovarian, lung, and stomach cancersBreast cancersLeukemiaMultiple 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



Nonreceptor tyrosine kinase

abl Translocation

Chronic myeloid leukemiaAcute lymphoblastic leukemia

Nuclear regulatory proteins

Transcriptional activators

Myc N-myc

L-myc

TranslocationAmplification

Amplification

Burkitt lymphomaNeuroblastomaSmall cell carcinoma of lungSmall cell carcinoma of lung



Cell cycle regulators

Cyclins

Cyclin-dependent kinase

Cyclin D

CDK4

TranslocationAmplificationAmplification or point mutation

Mantle cell lymphoma Breast, liver, esophageal cancersGlioblastoma, 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.

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： PDGF-β 链 sis 过度表达星形细胞瘤、骨肉瘤 FGF HST-1 过度表达胃癌 INT-2 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-B2 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 CDK4 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)

(2) Cancer suppressor genes

① Molecules that regulated nuclear transcription and cell cycle

Rb gene: 13q14, G1 × SP53 gene: 17p13.1, related to 50%

of human tumorsBRCA- l gene: 17q12-21,BRCA-2 gene: 13q12-13

② Molecules that regulated signal transduction

NF-1 gene: 17q11.2

APC gene: 5q21

③ Cell surface receptors

SMAD2 gene:

SMAD4 gene:

DCC gene: 18q21

④ Other tumor suppressor genes

NF- 2 gene

VHL gene: 3p

PTEN gene: 10q23,

WT- 1 gene: 11p13

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 inhibitionCell adhesion

Carcinomas of colonCarcinoma 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 Unknown Schwannomas and meningiomas

Neurofibromatosis type Ⅱ; acoustic schwannomas and meningiomas


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


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 DNA repair Carcinomas of male and female breast

(3) Genes that regulate apoptosis

Inhibit apoptosis: bc1- 2 gene (18q21), bc1-Xl

Favor apoptosis: bax, bad, bc1-xS

(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.

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.

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.

(5) Telomere and tumor

telomerase activity increased

in majority of human tumors.

(6) (6) Molecular Basis of Molecular Basis of Multistep Multistep CarcinogenesisCarcinogenesis

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.

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.

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.

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.

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.

CARCINOGEN

Electrophilic intermediates

Binding to DNA: Adduct formation

Permanent DNA lesion: Initiated cell

Cell proliferaion: Altered differentiation

PRENEOPLASTIC CLONE

MALIGNANT NEOPLASM

Additionalmutations

Metabolic activation Excreti

Proliferation

Normal cell

Cell death

DNA

repairINITIATION

PROMOTION


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

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.

③ Aromatic amines( 芳族胺 )

and azo dyes

a. Mainly in liver

b. Can induce hepatocellular carcinomas and bladder cancer

④ Naturally occurring carcinogens

Aflatixi( 黄曲霉毒素 )B1 and HBV related to hepatocellular carcinoma

⑤ Nitrosamine( 亚硝胺 ) and amidesRelated to gastric carcinoma

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

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.

(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.

(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

② DNA oncogenic viruses

Transforming DNA viruses form stable association with the host cell genome and are important for cell transformation.

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.

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.

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)

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.

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 15q26.1. 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

(2) Host defense against tumors- Tumor immunity

① Tumor antigen

a. Tumor- specific antigen (TSA)

b. Tumor- associated antigen (TAA)

Embryonic antigens: e. g. AFP, CEADifferentiation antigens: CD10Tissue-specific antigens: e. g.

tyrosinaseAntigens resulting from mutations: e.

g. mutatead P53, K-ras, CDK4Overexpressed antigens: e. g, c-erbB2

protein Viral antigens: e. g. E7

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

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.

(3) The Others

① Endocrine ② Sex ③ Age ④ Ethnic ⑤ Geography

6.5Etiology&Oncogenesis

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