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Cancer Etiology 1. Introduction 2. Chemical Factors in Carcinogenesis 3. Physical Factors in Carcinogenesis 4. Viral Oncogenesis 5. Genetic Predisposition. 邵吉民,教授,病理学与病理生理学系 [email protected] Introduction. Tumor Benign tumor Malignant tumor. Cancer Incidence and Mortality

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Cancer Etiology1. Introduction 2. Chemical Factors in Carcinogenesis 3. Physical Factors in Carcinogenesis4. Viral Oncogenesis5. Genetic Predisposition

邵吉民,教授,病理学与病理生理学系

[email protected]

slide2

Introduction

  • Tumor
  • Benign tumor
  • Malignant tumor
slide3

Cancer Incidenceand Mortality

  • Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012.
  • CA Cancer J Clin. 2012;62(1):10-29.
  • 1,638,910 new cancer cases and 577,190 deaths from cancer are projected to occur in USA in 2012.
  • One in 4 deaths in USA is due to cancer.
  • 2010年国际抗癌联盟(UICC):
  • 2008年全世界1270万新增癌症患者,死亡人数760万。
  • 全国肿瘤登记中心《2012中国肿瘤登记年报》
  • 每年新发肿瘤病例约312万例,每天约8550人;
  • 每年因癌死亡270万例,居民因癌死亡率13%,即每7-8人中有1人因癌死亡。
  • 恶性肿瘤发病:第一位肺癌,其次胃癌、结直肠癌、肝癌和食管癌;
  • 恶性肿瘤死亡:第一位肺癌,其次肝癌、胃癌、食管癌和结直肠癌;
  • 中国近20年来癌症呈现年轻化及发病率和死亡率“三线”走高的趋势。癌症种类呈现地域化特点。
slide4

History of Cancer Research

Kiberstis P, Marshall E. Cancer crusade at 40. Celebrating an anniversary. Introduction.Science. 2011;331(6024):1539.

chemical carcinogenesis

Chemical Carcinogenesis

  • Multi-stage Theory of Chemical Carcinogenesis
  • Classification of chemical carcinogens
  • Mechanisms of Chemical Carcinogenesis
  • DNA Damage Induced by Ultimate Carcinogens
  • DNA Repair
multi stage theory of chemical carcinogenesis
Multi-stage Theory of Chemical Carcinogenesis

Initiation-----------Genetic events

Chemical Carcinogens (Direct and Indirect Carcinogens)

Promotion -------Epigenetic events

Tumor promoters

  • Murine skin carcinogenesis model:
    • A single dose of polycyclic aromatic hydrocarbon (PAH, initiator)
    • Repeated doses of croton oil (promoter)

Malignant conversion

Progression ------Genetic and epigenetic events

6

initiation
Initiation
  • Irreversible genetic damage:

A necessary, but insufficient prerequisite for tumor initiation

  • Activation of proto-oncogene, inactivation of a tumor suppressor gene, and etc

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promotion
Promotion
  • Promotion: Selective expansion of initiated cells, which are at risk of further genetic changes and malignant conversion
  • Promoters are usually nonmutagenic, not carcinogenic alone, often do not need metabolic activation, can induce tumor in conjuction with a dose of an initiator that is too low to be carcinogenic alone
  • Chemicals capable of both initiation and promotion are called complete carcinogens: benzo[a]pyrene and 4-aminobiphenyl

9

malignant conversion
Malignant conversion
  • The transformation of a preneoplastic cell into that expresses the malignant phenotype
  • Further genetic changes
  • Reversible
  • The further genetic changes may result from infidelity of DNA synthesis
  • May be mediated through the activation of proto-oncogene and inactivation of tumor-suppressor gene

10

progression
Progression
  • The expression of malignant phenotype, the tendency to acquire more aggressive characteristics, Metastasis
  • Propensity for genomic instability and uncontrolled growth
  • Further genetic changes: the activation of proto-oncogenes and the inactivation of tumor-suppressor genes

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Activation of proto-oncogenes:
    • Point mutations: ras gene family, hotspots
    • Overexpression:
      • Amplification
      • Translocation
  • Loss of function of tumor-suppressor genes: usually a bimodal fashion
    • Point mutation in one allele
    • Loss of second allele by deletion, recombinational event, or chromosomal nondisjunction

12

gene environmental interactions
Gene-environmental interactions
  • The metabolism of xenobiotics by biologic systems
    • Individual variation
    • The competition between activation and detoxication
  • The alteration of genes by xenobiotics

13

classification of chemical carcinogens
Classification of chemical carcinogens

1. Based on mechanisms

  • Genotoxic carcinogen (DNA-reactive)
  • Direct-acting:

intrinsically reactive

N-methyl-N’-nitro-N-nitrosoguanidine (MNNG),

methyl methanesulfonate (MMS),

N-ethyl-N-nitrosourea (ENU), nitrogen and sulfur mustards

  • Indirect-acting:

require metabolic activation by cellular enzyme to form the DNA-reactive metabolite (members of the cytochrome P450 family)

benzo[a]pyrene, 2-acetylaminofluorene, benzidine, Aflatoxin B1, B2.

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(2) Epigenetic carcinogens
  • Promotes cancer in ways other than direct DNA damage/ do not change the primary sequence of DNA
  • Alter the expression or repression of certain genes and cellular events related to proliferation and differentiation
  • Promoters, hormone modifying agents, peroxisome proliferators, cytotoxic agents, and immunosuppressors
  • Organochlorine pesticides, [saccharin], estrogen, cyclosporine A, azathioprine

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slide17

2. Based on sturcture

(1) Nitrosamines (NA)

MNNG, MMS (direct carcinogen)

(2) Polycyclic aromatic hydrocarbons (PAH)

Benzo(a)pyrene (indirect carcinogen)

(3) Aromatic amines (AA)

2-acetylaminofluorene, benzidine (indirect carcinogen)

(4) Aflatoxin (AF)

(5) Inorganic elements and their compounds: arsenic, chromium,

and nickel are also considered genotoxic agents

17

mechanisms of initiation in chemical carcinogenesis
Mechanisms of Initiation in Chemical Carcinogenesis

(1) DNA damages:

Pro-carcinogen metabolic activation (Phase I and II)

Ultimate carcinogen (electrophiles)

Interaction with macromolecules (nucleophiles)

DNA damage, mutations, chromosomal aberrations, or cell death

(2) Epigenetic changes

(3)Activation of oncogenes; inactivation of tumor suppressor genes

19

direct chemical carcinogens
Direct Chemical Carcinogens
  • (1) Alkylating agents are electrophilic compounds with affinity for
  • nucleophilic centers in organic macromolecules.
  • [Fu D, Calvo JA, Samson LD. Balancing repair and tolerance of DNA damage caused by alkylating agents. Nat Rev Cancer. 2012 Jan 12;12(2):104-20. doi: 10.1038/nrc3185.]
  • (2) These agents can be either monofunctional or bifunctional.
    • ---Monofunctional alkylating agentshave a single reactive group and thus interact covalently with single nucleophilic centers in DNA (although varied).
  • such as MNNG
    • ---Bifunctional alkylating agentshave two reactive groups, and each molecule is potentially able to react with two sites in DNA.
    • Interstrand DNA cross-link: the two sites are on opposite polynucleotide strands;
    • Intrastrand cross-link: on the same polynucleotide chain of a DNA duplex.
    • such as Nitrogen and sulfur mustard, mitomycin,cis-platinum

20

slide21

---Monofunctional alkylating agents

Numerous potential reaction sites for alkylation have been identified in all four bases of DNA (not all of them have equal reactivity:

21

MNNG N-Methyl-N-nitroso-N\'-nitroguanidine

slide24

BPDE binds DNA covalently, resulting in bulky adduct damage

BPDE intercalates into dsDNA non-covalently, leading to conformational abnormalities

types of dna damage induced by ultimate carcinogens
Types of DNA Damage Induced by Ultimate Carcinogens
  • DNA Adduct Formation
  • DNA Break

Single Strand Break

Double Strand Break

  • DNA Linkage

DNA-DNA linkage

DNA-protein Linkage

  • Intercalation

Bulky aromatic-type adducts, Alkylation (small adducts),

Oxidation, Dimerization, Deamination

25

repair systems

DNA Repair

Repair systems
  • Direct DNA repair/ Direct reversal :
    • DNA alkyltransferase (O6-alkylguanine-DNA alkyl transferase)
    • One enzyme per lesion
  • Base excision repair (BER)
    • small adducts,
    • overlap with direct repair
    • glycosylase to remove the adducted base

26

slide27
Nucleotide excision repair (NER):
    • involves recognition, preincision, incision, gap-filling, and ligation,
    • large distortions
    • strand specific, the transcribed strand is preferentially repaired
    • xeroderma pigmentosum (XP): NER deficiency
  • Mismatch repair (MMR)
    • transition mispairs are more efficiently repaired (G-T or A-C) than transversion mispairs
    • microenvironment influences efficiency
    • similar to NER
    • involves the excision of large pieces of the DNA

27

slide28
Double-strand breaks (DSBs)
    • homologous recombination
    • non-homologous end joining (NHEJ): DNA-PK
  • Postreplication repair
    • a damage tolerance mechanism
    • occurs in response to replication of DNA on a damaged template
    • the gap
      • either filled through homologous recombination with parental strand
      • or insert an A residue at the single nucleotide gap

28

hormones and the etiology of cancer
Hormones and the etiology of cancer
  • Major carcinogenic consequence of hormone exposure: cell proliferation
  • The emergence of a malignant phenotype depends on a series ofsomatic mutation
  • Germline mutations may also occur
  • How to get exposure: contraceptives, hormone replacement therapy, or during prevention of miscarriage
  • Epidemiological studies
hormone related cancer
Hormone-related cancer
  • Breast cancer and estrogen
  • Endometrial cancer: Estrogen replacement therapy
  • Ovarian cancer: follicle stimulating hormone
  • Prostate cancer and androgen
  • Vaginal adenocarcinoma: in utero diethylstilbestrol (DES) exposure
other hormone related cancers
Other hormone-related cancers
  • Cervical cancer: OC use might increase the risk, still a lot complicating factors
  • Thyroid cancer: the pituitary hormone thyroid stimulating hormone (TSH)
  • Osteosarcoma: incidence associates with the pattern of childhood skeleton growth; and hormonal activity is a primary stimulus for skeleton growth
physical carcinogens
Physical carcinogens
  • Corpuscular radiations
  • Electromagnetic radiations (EMF)
  • Ultraviolet lights (UV)
  • Low and high temperatures
  • Mechanical traumas
  • Solid and gel materials
viral oncogenesis
Viral Oncogenesis
  • RNA Oncovirus (Retrovirus)
  • DNA Oncovirus

36

rna oncovirus

RNA Oncovirus

  • Retroviruses:
    • ssRNA viruses
    • Reverse transcriptase
    • Oncogenes
  • Rous sarcoma in chickens (RSV): in 1911
  • Human T-cell lymphotropic virus (HTLV-I,II)
  • Human immunodeficiency virus (HIV)
genome of rna oncovirus and gene products
Genome of RNA Oncovirus and Gene Products

Genome of Human T-cell Leukemia virus (HTLV)

40

life cycle
Life cycle
  • Receptor binding and membrane fusion
  • Internalization and uncoating
  • Reverse transcription of the RNA genome to form double-stranded linear DNA
  • Nuclear entry of the DNA
  • Integration of the linear DNA into host chromosomal DNA to form the provirus
  • Transcription of the provirus to form viral RNAs

Splicing and nuclear export of the RNAs

Translation of the RNAs to form precursor proteins

Assembly of the virion and packaging of the viral RNA genome

Budding and release of the virions

Proteolytic processing of the precursors and maturation of the virions

41

mechanisms of oncogenesis induced by rna oncovirus
Mechanisms of Oncogenesis Induced by RNA Oncovirus
  • Transducing Retrovirus

v-onc

  • cis-Activating Retrovirus

c-onc

  • trans-Activating Retrovirus

tax trans-acting x p40tax

rex repressive expression x p27rex,p21rex

43

slide44
Oncogene transduction
    • Acutely transforming in vivo and in vitro
    • Transform cells by the delivery (transduction) of an oncogene from the host cell (v-onc) to a target cell
    • Cause the formation of polyclonal tumors
    • Most of this group of viruses are replication defective (the requirement of a helper virus)
    • Examples:

RSV (v-src);

Abelson murine leukemia virus (v-Abl)

44

insertional activation
Insertional activation
  • Long latent periods, Less efficient
  • Do not induce transformation of cells in vitro
  • Usually are replication competent
  • No oncogenes
  • Tumors are usually monoclonal
  • Provirus (LTR) is found within the vincity of a proto-oncogene (c-myc)
  • Examples: lymphoid leukosis virus;

45

grow stimulation and two step oncogenesis
Grow stimulation and two-step oncogenesis
  • The defective spleen focus-forming virus (SFFV) and its helper, the Friend murine leukemia virus (Fr-MuLV)
  • Induce a polyclonal erythrocytosis in mice
  • Require the continued viral replication
  • A mutant env protein gp55 of SFFV binds and stimulated the erythropoietin receptor, thus inducing erythroid hyperplasia
  • Fr-MuLV or SFFV integration inactivates p53

46

transactivation
Transactivation
  • HTLV-1 and 2
  • Like cis-activation group: replication competent, carries no oncogene, induces monoclonal leukemia, and latent
  • Like transducing group: can immortalize cells in vitro, has no specific integration site
  • Unique 3’ genomic structure: the X region; Encodes at least three proteins: Tax (p40), Rex (p27, p21)
  • Tax is the focus
    • Transactivate the viral LTR, results in a 100- to 200-fold increase in the rate of proviral transcription
    • Transactivate cellular enhancers and promoters, including genes for IL-2, granulocyte-macrophage colony-stimulating factor (GM-CSF), c-fos, and others.

47

dna oncovirus
DNA Oncovirus

Papilloma virus

Polyoma virus

Adenovirus

Herpes virus: EB virus

Hepatitis B virus

48

mechanism of oncogenesis induced by dna oncovirus
Mechanism of Oncogenesis Induced by DNA Oncovirus

Transforming proteins

1. HPV E6 interact with P53

E7 interact with RB

2. Adenovirus E1a interact with RB

E1b

3. Polyoma virus

SV40 Large T interact with RB

Py virus Large and Middle T

Transcription activators

1. EB virus EBNA-2 and LMP

2. HBV p28 X protein

49

gene map and function of hpv
Gene Map and Function of HPV

ORF Function

E1 Virus proliferation

E2 Regulation of transcription

E5、E6、E7 Cell transformation

L1、L2 Encoding capsid protein

E4 Encoding late cytosolic protein

E3、E8 Unkown

  • E5: activates growth factor receptor
  • E6: ubiquitin-mediated degradation of p53
  • E7: binds and inactivates unphosphorylated pRb

50

genome and products of hbv
Genome and Products of HBV

Transforming gene: X gene

X protein activates gene transcription via XRE

51

genetic predisposition
Genetic Predisposition
  • Hereditary Cancer
  • Tumor Genetic Susceptibility

---Tumor susceptibility genes (Cytochrome P450 family, DNA repair genes, Tumor suppressor genes, etc)

  • Immunity
  • Hormones and metabolism
  • Psychological factors
  • others

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