Cancer Etiology 1. Introduction 2. Chemical Factors in
Carcinogenesis 3. Physical Factors in Carcinogenesis 4. Viral
Oncogenesis 5. Genetic Predisposition [email protected]
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2 Tumor Benign tumor Malignant tumor Introduction
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3 Cancer Incidence and 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 UICC 2008 1270 760 2012 312 8550 ; 270 , 13% 7-8 1 : ;
20
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4 History of Cancer Research Kiberstis P, Marshall E. Cancer
crusade at 40. Celebrating an anniversary. Introduction. Science.
2011;331(6024):1539.Cancer crusade at 40. Celebrating an
anniversary. Introduction.
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Chemical Carcinogenesis Multi-stage Theory of Chemical
Carcinogenesis Classification of chemical carcinogens Mechanisms of
Chemical Carcinogenesis DNA Damage Induced by Ultimate Carcinogens
DNA Repair
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66 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
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77
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88 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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99 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
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10 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
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11 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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12 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
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13 Gene-environmental interactions The metabolism of
xenobiotics by biologic systems Individual variation The
competition between activation and detoxication The alteration of
genes by xenobiotics
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14 Classification of chemical carcinogens 1. Based on
mechanisms (1)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[ ]pyrene,
2-acetylaminofluorene, benzidine, Aflatoxin B1, B2.
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15
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16 (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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17 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
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18
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19 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
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20 (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. ---M onofunctional
alkylating agents have a single reactive group and thus interact
covalently with single nucleophilic centers in DNA (although
varied). such as MNNG ---B ifunctional alkylating agents have 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 Direct Chemical
Carcinogens
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21 Numerous potential reaction sites for alkylation have been
identified in all four bases of DNA (not all of them have equal
reactivity: MNNG N-Methyl-N-nitroso-N'-nitroguanidine
---Monofunctional alkylating agents
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22 ---Bifunctional alkylating agents
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23 Indirect Chemical Carcinogens and Their Phase I Metabolic
derivatives
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24 BPDE binds DNA covalently, resulting in bulky adduct damage
BPDE intercalates into dsDNA non-covalently, leading to
conformational abnormalities
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25 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
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26 Repair systems Direct DNA repair/ Direct reversal : DNA
alkyltransferase (O 6 -alkylguanine-DNA alkyl transferase) One
enzyme per lesion Base excision repair (BER) small adducts, overlap
with direct repair glycosylase to remove the adducted base DNA
Repair
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27 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
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28 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
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29 Translesion DNA synthesis
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30 Hormones and the etiology of cancer Major carcinogenic
consequence of hormone exposure: cell proliferation The emergence
of a malignant phenotype depends on a series of somatic mutation
Germline mutations may also occur How to get exposure:
contraceptives, hormone replacement therapy, or during prevention
of miscarriage Epidemiological studies
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31 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
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32 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
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33 Physical factors in carcinogenesis
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34 Physical carcinogens Corpuscular radiations Electromagnetic
radiations (EMF) Ultraviolet lights (UV) Low and high temperatures
Mechanical traumas Solid and gel materials
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35
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36 Viral Oncogenesis RNA Oncovirus (Retrovirus) DNA
Oncovirus
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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)
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38 Classification of retrovirus
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39 Structure of RNA Oncovirus
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40 Genome of RNA Oncovirus and Gene Products Genome of Human
T-cell Leukemia virus (HTLV)
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41 Life cycle 1.Receptor binding and membrane fusion
2.Internalization and uncoating 3.Reverse transcription of the RNA
genome to form double-stranded linear DNA 4.Nuclear entry of the
DNA 5.Integration of the linear DNA into host chromosomal DNA to
form the provirus 6.Transcription of the provirus to form viral
RNAs 7.Splicing and nuclear export of the RNAs 8.Translation of the
RNAs to form precursor proteins 9.Assembly of the virion and
packaging of the viral RNA genome 10.Budding and release of the
virions 11.Proteolytic processing of the precursors and maturation
of the virions
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42 Replication of RNA Oncovirus
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43 Mechanisms of Oncogenesis Induced by RNA Oncovirus
Transducing Retrovirus v-onc cis-Activating Retrovirus c-onc
trans-Activating Retrovirus tax trans-acting x p40 tax rex
repressive expression x p27 rex, p21 rex
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44 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)
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45 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;
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46 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
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47 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.
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48 DNA Oncovirus Papilloma virus Polyoma virus Adenovirus
Herpes virus: EB virus Hepatitis B virus
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49 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
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50 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
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51 Genome and Products of HBV Transforming gene: X gene X
protein activates gene transcription via XRE
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52 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