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Environmental Carcinogenesis
Thomas Kensler, PhD Bloomberg School of Public Health
3
Lecture OutlineCancer - What is it? What causes it?Epidemiological evidence for a role of environment/life-style factors as causes of cancerMechanisms of carcinogenesis– Carcinogenic agents– Carcinogen bioactivation, DNA damage/repair– Molecular targets: oncogenes, tumor suppressor
genes
Multistage nature of carcinogenesisPrevention of carcinogenesis
Section A
Cancer: What It Is and What Causes It
5
Cancer: The Endpoint
What is it?– Group of diseases– Uncontrolled growth– Spread (invasion, metastasis)
6
Carcinogenesis: The Process
What causes it?– Exogenous: Chemicals, radiation,
viruses– Endogenous: Hormones, immune
dysfunction,– Inherited mutations (susceptibilities)
7
CANCER ARISES FROMTHE ACCUMULATION OF GENETIC DAMAGE
(only 5-15 % of cancer is due to inherited cancer
genes)
Public Domain
8
SINGLE AND SUSCEPTIBILITY GENES IN CANCER CAUSE
Single Susceptibility GeneDefinition Necessary & sufficient Alters risk but is neither
for disease necessary nor sufficientfor disease causation
Example BRCA (breast/ovary) CYP1A1 (lung)APC (polyposis coli) CYP2D6 (lung)RB (retinoblastoma) GST-M1 (lung, bladder)
Gene prevelence Low Often highGene type Mutation Polymorphism or mutationStudy setting Family Gen. population/epi. studiesStrength of association Very high Low to moderateAbsolute risk High LowPopulation attributable risk Low High
Gene-environment interaction 2° and variable 1° and implicit
Role of environmentalexposure 2° and variable Crucial
9
Risk of Breast Cancer Among BRCA1 or BRAC2 Mutation Carriers
JHSPH OpenCourseWare has removed this image because license for its use could not be secured.
See Figure 1A. King MC, et al. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2.
Science. 2003;302:643-646. Free with registration.
10
Influence of Birth Cohort on Risk of Breast Cancer in BRCA1 or BRCA2 Mutation Carriers
JHSPH OpenCourseWare has removed this image because license for its use could not be secured.
See Figure 1D. King MC, et al. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2.
Science. 2003;302:643-646. Free with registration.
11
Effect of Physical Activity on Risk of Breast Cancer in BRCA1 or BRCA2 Carriers
JHSPH OpenCourseWare has removed this image because license for its use could not be secured.
See Figure 1F. King MC, et al. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2.
Science. 2003;302:643-646. Free with registration.
12
SINGLE AND SUSCEPTIBILITY GENES IN CANCER CAUSE
Single Susceptibility GeneDefinition Necessary & sufficient Alters risk but is neither
for disease necessary nor sufficientfor disease causation
Example BRCA (breast/ovary) CYP1A1 (lung)APC (polyposis coli) CYP2D6 (lung)RB (retinoblastoma) GST-M1 (lung, bladder)
Gene prevelence Low Often highGene type Mutation Polymorphism or mutationStudy setting Family Gen. population/epi. studiesStrength of association Very high Low to moderateAbsolute risk High LowPopulation attributable risk Low High
Gene-environment interaction 2° and variable 1° and implicit
Role of environmentalexposure 2° and variable Crucial
13
Progression of Pre-Cancer to Cancer in Humans: A Multiyear Process
BreastBreast AtypicalHyperplasia
AtypicalHyperplasia DCISDCIS CancerCancer14-18 yrs14-18 yrs 6-10 yrs6-10 yrs
ColonColon AdenomaAdenoma5-20 yrs5-20 yrs
CervixCervix CIN ICIN I CIN III/CIS
CIN III/CIS9-13 yrs9-13 yrs 10-20 yrs10-20 yrs
ProstateProstate PINPIN LatentCarc.
LatentCarc.> 10 yrs> 10 yrs Clin.
Carc.Clin.Carc.3-15 yrs3-15 yrs20 yrs20 yrs
5-15 yrs5-15 yrs
14
Epidemiological Evidence
For a role of environmental-life factorsas causes of cancer– Epidemiology provides important
inferences and helps build hypotheses about the role of environmental factors in human carcinogenesis
15
Role of Environmental Agents in Human Cancer
Although overall cancer incidence is reasonably constant between countries, incidences of specific tumor types can vary up to several hundred-foldThere are large differences in tumor incidences within populations of a single country
Continued
16
Role of Environmental Agents in Human Cancer
Migrant populations assume the cancer incidence of their new environment within one to two generationsCancer rates within a population can change rapidly
17
TypeHigh
IncidenceLow
IncidenceRatio
(35-64 yrs)Breast USA Uganda 5Colon USA Nigeria 10Cervix Columbia Israeli Jews 15Rectum Denmark Nigeria 20Stomach Japan Uganda 25
Geographic Variation in the Incidence of Some Common Cancers
18
TypeHigh
IncidenceLow
IncidenceRatio
(35-64 yrs)Prostate US Blacks Norway 30Liver Mozambique Norway 70Skin Australia India >200Penis Uganda Israeli Jews 300
Geographic Variation in the Incidence of Some Common Cancers
19
Cancer Around the World Age Adjusted Mortality per 100,000
Population 46 Countries (1974–1975)
Stomach
0
10
20
30
40
50
60
Japan (1) USA (44)
Male Female
Breast
0
10
20
30
40
50
60
Japan(43)
USA (13) England(1)
20
Mortality from Stomach Cancer (Japan and California)
0
10
20
30
40
50
60
Age
Sta
ndar
dize
d M
orta
lity/
100,
000/
year
In Japan Immigrantsto CA
Born in CA
CaucasiansIn CA
M
F
Japanese
21
0
10
20
30
40
50
60
Age
Stan
dard
ized
M
orta
lity/
100,
000/
year
In Japan Immigrantsto CA
Bornin CA
Caucasiansin CA
Japanese
M F
Mortality From Colon Cancer (Japan and California)
22
0
10
20
30
40
50
60
Age
Sta
ndar
dize
d M
orta
lity/
100,
000/
yr
In Japan Immigrantsto CA
Born in CA
Caucasiansin CA
Japanese
M F
Mortality From Rectal Cancer (Japan and California)
23
Lung Cancer MortalityMale
1950 - 1969
1970 - 1994
Public Domain
24
Lung Cancer MortalityFemale
1950 - 1969
1970 - 1994
Public Domain
25
1970 - 1994
1950 - 1969
Colon Cancer Mortality Male
Public Domain
26Public Domain
27
Age-Adjusted Cancer Death Rates/100,000, US Males by Site, 1930–94
*
28
Per Capita Consumption of Different Forms of Tobaccoin the United States: 1880 -
1995
29
Age-Adjusted Cancer Death Rates/100,000, US Females by Site, 1930–94*
30
State Name Death Count Population Age Adjusted
Rate
District of Columbia 31,365 12,114,011 272.0
Delaware 28,898 13,174,117 241.1
Louisiana 169,699 86,260,188 236.6
Maryland 187,723 93,374,200 236.1
Kentucky 161,990 74,851,849 230.7
Maine 55,404 23,893,173 230.2
New Jersey 351,681 154,248,561 230.2
Nevada 44,249 23,522,411 226.6
Rhode Island 47,715 19,625,760 225.8
New Hampshire 42,737 21,176,058 225.8
Cumulative Cancer Mortality In the Worst 10 States and DC (1979-1998)
31
Maryland Cancer Mortality 1997
COLON ANDRECTUM
11.7%
LEUKEMIAS3.3%
PANCREAS4.7%
OVARY2.2%
BLADDER2.0%
ESOPHAGUS2.5%
STOMACH2.6%
PROSTATE6.4%
OTHER19.5%
LUNG ANDBRONCHUS
28.7%
BREAST8.5%
PHARYNX1.4%
MELANOMA1.2%
LIVER1.8%
NHL3.3%
32
Cancer Mortality Rates in Maryland by County, 1983–1987
s
So
152 184 161
191
168
185
185 184
163174
194
205
206
192
176
180214
201198
190203
176
195236
Rates are age-adjusted to US 1970 population; rates per 100,000 population
Data source: Maryland Center for Health Studies
Significantly higher than US Rate (171)
33
Breast Cancer Incidence, 1996-1997
88.9-91.2
91.2-107.7
107.7-116.1
116.1-132.7
132.7-143.8
SEER Incidence Rate: 113.9/100,000; Average 96-97
34
Breast Cancer Mortality, 1993-1997
Regions with rates that are statistically significantly higher than the US average
35
Prostate Cancer Incidence, 1996-1997
89-102.7
102.7-116
116-147.5
147.5-169.4
169.4-200
SEER Incidence Rate: 137.4; Average 96-97
36
Prostate Cancer Mortality, 1993-1997
Regions with rates that are statistically significantly higher than the US average
37
The Causes of Cancer Quantitative Estimates
of Avoidable Risks of Cancer in the United States
By comparison of cancer incidence in the U.S. and the lowest incidence areas of the world, Doll and Peto concluded that:– 80% of male cancers and 77% of
female cancers are potentially avoidable
38
Proportion of Cancer Deaths Attributed to Environmental Influences
38
Diet 35%
Tobacco 30%
Infection 10%
Reproductive and sexual behavior 7%
Occupation 4%
Geophysical factors 3%
Alcohol 3%
Pollution 2%
Medicines & medicinal procedures 1%
Industrial products <1%
Food additives <1%
Data Source: Doll and Peto
39
Historical Perspective
1713: Ramazzini– Noted that nuns exhibited a higher
frequency of breast cancer than other women; attributed it to celibate life
1761: Hill– Associated the use of tobacco snuff with
cancer of the nasal passages
Continued
40
Historical Perspective
1775: Pott– Noted the occurrence of soot-related
cancer in chimney sweeps1894: Unna– Associated sunlight exposure with skin
cancer
Continued
41
Historical Perspective
1895: Rehn– Associated occupational exposure to
aromatic amine dyes with bladder cancer
1915: Ichikawa– First experimental production of tumors
in animals (application of coal tar to ears of rabbit)
Continued
Section B
Mechanisms of Carcinogenesis
43
The Causes of Cancer
BreathingEatingDrinkingRadiationSexDoctorsParents
44
Carcinogenic Agents
Physical agents– X-rays: breast, leukemias– Ultraviolet light: skin: non-melanoma
and melanoma– Asbestos: lung
Continued
45Continued
Carcinogenic Agents
Biological agents– Viruses
• RNA tumor viruses (ex.: Human T-cell leukemia virus—HIV/HTLV)
• DNA tumor viruses (ex.: Hepatitis B and C: liver cancer; papilloma viruses: cervical cancer; Epstein-Barr virus: Burkitt’s lymphoma)
46Continued
Carcinogenic Agents
Biological agents– Bacteria
• Helicobacter pylori (Ex.: Stomach cancer)
47
Carcinogenic Agents
Chemicals– Inorganic: Arsenic, cadmium,
chromium, nickel, etc.– Organic: Polycyclic aromatic
hydrocarbons, heterocyclic amines, aflatoxin, nitrosamines, etc.
– Hormones: DES, ethinyl estradiol, estradiol, tamoxifen, etc.
48
Selected Human CarcinogensOccupational Medicinal Environmental
Aflatoxins ×4-Aminobiphenyl ×Arsenic compounds × × ×Asbestos × ×Benzene × ×Benzidine ×Bis-2-chloroethylsulfide (mustard gas) ×Bis-chloromethyl methyl ether ×Chromium compounds ×Cyclophosphamide ×Diethylstilbestrol ×Melphalan ×b-Napthylamine ×N,N-bis-2-chlorotheyl 2-naphthyl amine ×Vinyl chloride ×
49
Naturally Occurring Carcinogens
Microorganisms– Alfatoxins– Sterigmatocytin– Ochratoxin A– T-2 toxin– Luteoskyrin– Islanditoxin– Griseofulving– Actinomycins– Daunomycin– Azaserine– Streptozotocin
Plants– Pyrrolizidine– Mushroom toxins
(hydrazines)– Safrole– Bracken fern– Betel nut– Cycasin– Tannins– Goitrogen (thiourea)– Tobacco, snuff– Coffee (?)
Section C
Multistage Nature of Carcinogenesis I
51
Multistage Carcinogenesis
51
52
Mechanisms of Chemical Carcinogenesis
Activation of carcinogens by biotransformation– Molecular targets: DNA
• Types of DNA damage• DNA repair processes• Gene targets: cellular and proto-
oncogenes, and tumor suppressor genes
Multistage carcinogenesis
53
Enzymatic Activation/Inactivation of BP
54
Reactive Groups Added During Bioactivation
55
Sites for Carcinogen-DNA Adducts
O
H2 N N
HNN
N
DNA
2
1
4
3
6
5
8
7
9
III
I
II
I. Alkylating Agents, MycotoxinsII. Aromatic AminesIII. Polycyclic Aromatic Hydrocarbons, Alkenylbenzenes
56
Examples of Carcinogen-DNA Adducts
57
Examples of DNA Damage
Break– single strand– double Strand
Crosslink– DNA-protein– intra-protein– intra-strand
Specific bindingBase alterationBase detachmentIntercolation
58
DNA Repair Processes
Direct damage reversal– Ex.: AlkyltransferasesBase excision repair– Ex.: Glycosylases and
apurinic/apyrimidinic– Endonucleases
Source Pitot & Dragan. In Casarett & Doull, 1996 Continued
59
DNA Repair Processes
Nucleotide excision repair– Ex.: repair of pyrimidine dimers– Repair of “bulky” adductsRecombination: Postreplication repairMismatch repair– Ex.: Repair of deaminated 5-
methylcytosine
Source Pitot & Dragan. In Casarett & Doull, 1996
6060
61
62
Genotoxicity
Mutagenesis– Occurrence of “point” or “gene-locus”
mutation (base pairs), substitution, and small deletions or additions
Clastogenesis– Occurrence of chromosomal breaks
resulting in gain, loss, or rearrangement of pieces of chromosome
Continued
63
Genotoxicity
Aneuplodization– Gain or loss of one or more
chromosomes
64
Genetic Damage and Cancer
Gain of function: (proto-oncogenes and oncogenes)– Point mutation– Translocation– AmplificationLoss of function: (tumor suppressor genes)– Deletion– Translocation– Mutation
65
Ways By Which Different Oncogene Products May Disrupt Normal Regulation of Cell Growth
Growth Factors
Receptors
2nd Messengers
DNA Synthesis
Oncogenes
66
A. Oncogenes
Functions of Gene Product Genes Cell Localization
Growth Factors sis, fgf ExtracellularReceptor/protein tyrosine kinases met, neu Extra cell/cell membraneProtein tyrosine kinases src, ret Cell membrane/cytoplasmicMembrane-associated G proteins ras, gip-2 Cell membrane/cytoplasmicCytoplasmic protein serine kinases raf, pim-1 CytoplasmicNuclear transcription factors myc, fos, jun NuclearUnknown, undetermined bcl-2, crk Mitochondrial, cytoplasmic
Functions of Representative Oncogenes and Tumor
Suppressor Genes
Continued
67
B. Tumor Suppressor genes
Functions of Gene Product Genes Cell Localization
GTPase activation NF1 Cell membrane/cytoplasmicCell cycle-regulated nucleartranscriptional repressor RB-1 Nuclear
Cell cycle-regulated nucleartranscription factor p53 Nuclear
Zinc finger transcription factor WT1 NuclearMismatch DNA repair hMLH1 NuclearZinc finger transcription factor (?) BRCA1 Nuclear
Functions of Representative Oncogenes and Tumor
Suppressor Genes
68
Role of Estrogen in Mammary Carcinogenesis
Section D
Multistage Nature of Carcinogenesis II
70
Multistage Carcinogenesis
70
71
Mechanisms of Chemical Carcinogenesis
Activation of carcinogens by biotransformationMultistage carcinogenesis– Initiation: somatic cell mutation– Promotion: clonal expansion of initiated
cells– Progression: evolution of neoplastic
phenotype (angiogenesis, invasiveness, metastasis)
72
Initiation and Promotion Operational Definitions
Many Tumors
No Tumors
Initiator
Promotor
73
Mechanisms for Selection and Clonal Expansion by
Tumor Promoters
74
Chemical Structures of Some Tumor Promoters
75
Promoters Can Determine the Target Site for Tumors
Initiator Tumor Promoter Target Organ
2-AAF or BBN phenobarbitalsaccharin
liverbladder
N-methylnitroso- urea
phenobarbitalsaccharin
liver & thyroidbladder
76
Neoplasms Associated with Prolonged Contact With Promoting Agents in the Environment
Agent Resulting NeoplasmDietary fat Mammary adenocarcinomaHigh caloric intake Increased cancer incidence in generalCigarette smoke Bronchogenic carcinoma (esophageal and
bladder cancer)Asbestos Bronchogenic carcinoma & mesotheliomaHalogenated hydrocarbons Liver
(dioxin, PCBs)Phorbol esters Esophageal cancer (?)Saccharin Bladder cancer*Phenobarbital Liver*Prolactin Mammary adenocarcinomaSynthetic estrogens Liver adenomasAlcoholic beverages Liver and esophageal cancer
* Promotion demonstrated in experimental animals, but not in humans
77
Lung Cancer
Since 1987, more women have died of lung cancer than breast cancerRisk factors: SMOKING, industrial exposures, radiation exposureEarly detection: DifficultPrevention: STOP SMOKING!
78
Smoking and Lung Cancer
79
Relative Risk for Developing Lung Cancer Compared with the Risk of Dying from Lung Cancer for a
Nonsmoker not Exposed to Asbestos
87
53
11
5
0 20 40 60 80 100
Asbestos workers smoking 1pack/day
Smoking asbestos workers
Smokers not exposed to asbestos
Nonsmoking asbestos worker
Times Higher
Source: Report of the Surgeon General, 1985
80Duration of Cessation (years)
MO
RTA
LITY
RA
TE R
ATI
O(fo
rmer
sm
oker
/nev
er s
mok
er)
0
5
10
15
20
25
30
5 10 15 20 25
1-9
10-19
2021-39
40+ # cigarettes per day
EFFECT OF SMOKING CESSATION ON MORTALITYFROM LUNG CANCER
81
Multistage Carcinogenesis
81
82
Tumor Progression
Conversion of benign tumor to malignancyDNA-damaging agents are good progressors– Alkylating agents (mutagens)– H2 02 and organic peroxides– Radiation
83
Malignant Conversion by Benzoyl Peroxide
84Continued
Morphological and Biological Characteristics of Initiation, Promotion, and Progression
INITIATION PROMOTION PROGRESSIONIrreversible Operationally reversible
both at the level of gene expression and at the cellular level
Irreversible
Initiated “stem cell” not morphologically identifiable
Promoted cell population dependent on continued administration of promoting agent
Morphologically discernible alteration in cellular structure resulting from karyotypic instability
Efficiency sensitive to xenobiotic and other chemical factors
Efficiency sensitive to aging and dietary and hormonal factors
Growth of altered cells sensitive to environ mental factors during early phase of this stage
Spontaneous (endogenous) occurrence of initiated cells
Endogenous promoting agents may effect “spontaneous” promotion
85
Morphological and Biological Characteristics of Initiation, Promotion, and Progression
INITIATION PROMOTION PROGRESSION
Requirement for cell division for “fixation”
Dose-response not exhibiting a readily measurable threshold
Dose response exhibits measurable threshold and maximal effect
Benign or malignant neoplasms observed in this stage
Relative potency of initiators dependent on quantitation of preneoplastic lesions after defined period of promotion
Relative potency of promoters measured by their effectiveness in causing an expansion of the initiated cell population
“Progressor” agents advance promoted cells into this stage
86
Some Cellular and Molecular Mechanisms in Multistage Carcinogenesis
INITIATION PROMOTION PROGRESSION
Simple mutations (transitions transversions, small deletions, etc.) involving the cellular genome
Reversible enhancement or repression of gene expression mediated via receptors specific for the individual promoting agent
Complex genetic alterations (chromosomal translocations, deletions, gene amplification, recombination, etc.) resulting from evolving karyotypic instability
In some species and tissues point mutations in protooncogenes and/or oncogenes
Inhibition of apoptosis by promoting agent; selective cytotoxicity to non-initiated cells
Irreversible changes in gene expression, including fetal gene expression, altered major histocompatibility complex (MHC) gene expression, and ectopic hormone production
Continued
87
Some Cellular and Molecular Mechanisms in Multistage Carcinogenesis
INITIATION PROMOTION PROGRESSION
Mutations in genes of signal transduction pathways that may result in an altered phenotype
No direct structural alteration in DNA from action or metabolism of promoting agent
Selection of neoplastic cells for optimal growth genotype phenotype in response to the cellular environment and including the evolution of karyotypic instability
88
Classification of Chemical Carcinogens In Relation to Their Action on One or More
Stages of Carcinogenesis
Initiating agent (incomplete carcinogen): A chemical capable only of initiating cellsPromoting agent: A chemical capable of causing the expansion of initiated cell clones
Continued
89
Progressor agent: A chemical capable of converting an initiated cell or a cell in the stage of promotion to a potentially malignant cell
Continued
Classification of Chemical Carcinogens In Relation to Their Action on One or More
Stages of Carcinogenesis
90
Complete carcinogen: A chemical possessing the ability to induce cancer from normal cells, usually with properties of initiating, promoting, and progressor agents
Classification of Chemical Carcinogens In Relation to Their Action on One or More
Stages of Carcinogenesis
91
Prevention of Carcinogenesis
Affordable cancer = Prevention + Protection
92
Prevention
Elimination of carcinogenic influences(e.g., industrial carcinogens, cigarette smoking, radiation– Knowledge of identity of carcinogen is
essential
93
Protection
Measures designed to interrupt the carcinogenic process without specific efforts to identify or eliminate carcinogenic influences (e.g., dietary measures)– Knowledge of identity of carcinogen is
desirable
94
Key Points
Environmental factors may contribute to 3/4 of all human cancersChemicals, viruses, and radiation can be carcinogenicDNA is a major target for carcinogens– With damage leading to gain or loss of
function of key genes
Continued
95
Key Points
Carcinogenesis is a long, multistage process yielding a heterogeneous family of diseases: CancerMost cancer is, in theory, preventable