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  • 1. This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike License. Your use of thismaterial constitutes acceptance of that license and the conditions of use of materials on this site.Copyright 2008, The Johns Hopkins University and Thomas Kensler. All rights reserved. Use of these materialspermitted only in accordance with license rights granted. Materials provided “AS IS”; no representations orwarranties provided. User assumes all responsibility for use, and all liability related thereto, and must independentlyreview all materials for accuracy and efficacy. May contain materials owned by others. User is responsible forobtaining permissions for use from third parties as needed.
  • 2. Environmental Carcinogenesis Thomas Kensler, PhD Bloomberg School of Public Health
  • 3. Lecture OutlineCancer - What is it? What causes it?Epidemiological evidence for a role ofenvironment/life-style factors as causes ofcancerMechanisms of carcinogenesis– Carcinogenic agents– Carcinogen bioactivation, DNA damage/repair– Molecular targets: oncogenes, tumor suppressor genesMultistage nature of carcinogenesisPrevention of carcinogenesis 3
  • 4. Section ACancer: What It Isand What Causes It
  • 5. Cancer: The EndpointWhat is it?– Group of diseases– Uncontrolled growth– Spread (invasion, metastasis) 5
  • 6. Carcinogenesis: The ProcessWhat causes it?– Exogenous: Chemicals, radiation, viruses– Endogenous: Hormones, immune dysfunction,– Inherited mutations (susceptibilities) 6
  • 7. CANCER ARISES FROM THE ACCUMULATIONOF GENETIC DAMAGE(only 5-15 % of cancer is due to inherited cancer genes) 7 Public Domain
  • 8. SINGLE AND SUSCEPTIBILITY GENES IN CANCER CAUSE Single Susceptibility GeneDefinition Necessary & sufficient Alters risk but is neither for disease necessary nor sufficient for disease causationExample 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 HighGene-environment interaction 2° and variable 1° and implicitRole of environmental exposure 2° and variable Crucial 8
  • 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. 9
  • 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. 10
  • 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. 11
  • 12. SINGLE AND SUSCEPTIBILITY GENES IN CANCER CAUSE Single Susceptibility GeneDefinition Necessary & sufficient Alters risk but is neither for disease necessary nor sufficient for disease causationExample 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 HighGene-environment interaction 2° and variable 1° and implicitRole of environmental exposure 2° and variable Crucial 12
  • 13. Progression of Pre-Cancer to Cancer in Humans: A Multiyear Process Atypical Atypical Breast Breast 14-18 yrs DCIS 6-10 yrs 6-10 yrs Cancer Hyperplasia Hyperplasia 14-18 yrs DCIS CancerCervix CIN I I 9-13 yrs CIN III/ CIN III/ 10-20 yrsCervix CIN 9-13 yrs 10-20 yrs CIS CIS Colon Colon 5-20 yrs 5-20 yrs Adenoma Adenoma 5-15 yrs 5-15 yrs Latent Latent Clin. Clin.Prostate Prostate 20 yrs 20 yrs PIN > 10 yrs > 10 yrs 3-15 yrs 3-15 yrs PIN Carc. Carc. Carc. Carc. 13
  • 14. Epidemiological EvidenceFor 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 14
  • 15. Role of Environmental Agents in Human CancerAlthough overall cancer incidence isreasonably constant between countries,incidences of specific tumor types can varyup to several hundred-foldThere are large differences in tumorincidences within populations of a singlecountry Continued 15
  • 16. Role of Environmental Agents in Human CancerMigrant populations assume the cancerincidence of their new environment withinone to two generationsCancer rates within a population canchange rapidly 16
  • 17. Geographic Variation in theIncidence of Some Common Cancers High Low Ratio Type Incidence Incidence (35-64 yrs) Breast USA Uganda 5 Colon USA Nigeria 10 Cervix Columbia Israeli Jews 15 Rectum Denmark Nigeria 20 Stomach Japan Uganda 25 17
  • 18. Geographic Variation in theIncidence of Some Common Cancers High Low Ratio Type Incidence Incidence (35-64 yrs) Prostate US Blacks Norway 30 Liver Mozambique Norway 70 Skin Australia India >200 Penis Uganda Israeli Jews 300 18
  • 19. Cancer Around the World Age Adjusted Mortality per 100,000 Population 46 Countries (1974–1975) Stomach Breast60 6050 Male Female 5040 4030 3020 2010 100 0 Japan (1) USA (44) Japan USA (13) England (43) (1) 19
  • 20. Mortality from Stomach Cancer (Japan and California) 60Mortality/100,000/year 50 Age Standardized 40 M 30 20 F 10 0 In Japan Immigrants Born Caucasians to CA in CA In CA Japanese 20
  • 21. Mortality From Colon Cancer (Japan and California) 60Mortality/100,000/year 50 Age Standardized 40 30 20 M F 10 0 In Japan Immigrants Born Caucasians to CA in CA in CA Japanese 21
  • 22. Mortality From Rectal Cancer (Japan and California) 60Mortality/100,000/yr 50 Age Standardized 40 30 20 10 M F 0 In Japan Immigrants Born Caucasians to CA in CA in CA Japanese 22
  • 23. Lung Cancer Mortality Male 1950 - 1969 1970 - 1994Public Domain 23
  • 24. Lung Cancer Mortality Female 1950 - 1969 1970 - 1994Public Domain 24
  • 25. Colon Cancer Mortality Male 1950 - 1969 1970 - 1994Public Domain 25
  • 26. Public Domain 26
  • 27. Age-Adjusted Cancer Death Rates/100,000, US Males by Site, 1930–94 * 27
  • 28. Per Capita Consumption of Different Forms of Tobacco in the United States: 1880 - 1995 28
  • 29. Age-Adjusted Cancer Death Rates/100,000, US Females by Site, 1930–94* 29
  • 30. Cumulative Cancer Mortality In the Worst 10 States and DC (1979-1998) Death Age Adjusted State Name Population Count RateDistrict 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 30
  • 31. Maryland Cancer Mortality 1997 MELANOMA LUNG AND PHARYNX 1.2% OTHER BRONCHUS 1.4% 19.5% 28.7% LIVER COLON AND 1.8% RECTUMBLADDER 11.7% 2.0%OVARY BREAST 2.2% 8.5%ESOPHAGUS NHL PROSTATE 2.5% 3.3% PANCREAS 6.4% STOMACH LEUKEMIAS 2.6% 3.3% 4.7% 31
  • 32. Cancer Mortality Rates in Maryland by County, 1983–1987 184 161 184 152 168 185 191 185 236 195 174 163 205 176 s Significantly higher than US Rate (171) 194 203 190 176 206 198Rates are age-adjusted to US 1970 201population; rates per 100,000 192population 214 180 SoData source: Maryland Center forHealth Studies 32
  • 33. Breast Cancer Incidence, 1996-1997 88.9-91.2 91.2-107.7 107.7-116.1 116.1-132.7 132.7-143.8SEER Incidence Rate: 113.9/100,000; Average 96-97 33
  • 34. Breast Cancer Mortality, 1993-1997 Regions with rates that are statistically significantly higher than the US average 34
  • 35. Prostate Cancer Incidence, 1996-1997 89-102.7 102.7-116 116-147.5 147.5-169.4 169.4-200SEER Incidence Rate: 137.4; Average 96-97 35
  • 36. Prostate Cancer Mortality, 1993-1997Regions with rates that are statisticallysignificantly higher than the US average 36
  • 37. The Causes of Cancer Quantitative Estimatesof Avoidable Risks of Cancer in the United StatesBy comparison of cancer incidence in theU.S. and the lowest incidence areas of theworld, Doll and Peto concluded that:– 80% of male cancers and 77% of female cancers are potentially avoidable 37
  • 38. Proportion of Cancer Deaths Attributed to Environmental Influences 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 38
  • 39. Historical Perspective1713: Ramazzini – Noted that nuns exhibited a higher frequency of breast cancer than other women; attributed it to celibate life1761: Hill – Associated the use of tobacco snuff with cancer of the nasal passages Continued 39
  • 40. Historical Perspective1775: Pott – Noted the occurrence of soot-related cancer in chimney sweeps1894: Unna – Associated sunlight exposure with skin cancer Continued 40
  • 41. Historical Perspective1895: Rehn – Associated occupational exposure to aromatic amine dyes with bladder cancer1915: Ichikawa – First experimental production of tumors in animals (application of coal tar to ears of rabbit) Continued 41
  • 42. Section BMechanisms of Carcinogenesis
  • 43. The Causes of CancerBreathingEatingDrinkingRadiationSexDoctorsParents 43
  • 44. Carcinogenic AgentsPhysical agents– X-rays: breast, leukemias– Ultraviolet light: skin: non-melanoma and melanoma– Asbestos: lung Continued 44
  • 45. Carcinogenic AgentsBiological 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) Continued 45
  • 46. Carcinogenic AgentsBiological agents– Bacteria • Helicobacter pylori (Ex.: Stomach cancer) Continued 46
  • 47. Carcinogenic AgentsChemicals– Inorganic: Arsenic, cadmium, chromium, nickel, etc.– Organic: Polycyclic aromatic hydrocarbons, heterocyclic amines, aflatoxin, nitrosamines, etc.– Hormones: DES, ethinyl estradiol, estradiol, tamoxifen, etc. 47
  • 48. Selected Human Carcinogens Occupational Medicinal EnvironmentalAflatoxins ×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 × 48
  • 49. Naturally Occurring CarcinogensMicroorganisms Plants– Alfatoxins – Pyrrolizidine– Sterigmatocytin – Mushroom toxins– Ochratoxin A (hydrazines)– T-2 toxin – Safrole– Luteoskyrin – Bracken fern– Islanditoxin – Betel nut– Griseofulving – Cycasin– Actinomycins – Tannins– Daunomycin – Goitrogen (thiourea)– Azaserine – Tobacco, snuff– Streptozotocin – Coffee (?) 49
  • 50. Section CMultistage Nature of Carcinogenesis I
  • 51. Multistage Carcinogenesis 51
  • 52. Mechanisms of Chemical CarcinogenesisActivation of carcinogens bybiotransformation – Molecular targets: DNA • Types of DNA damage • DNA repair processes • Gene targets: cellular and proto- oncogenes, and tumor suppressor genesMultistage carcinogenesis 52
  • 53. Enzymatic Activation/Inactivation of BP 53
  • 54. Reactive Groups Added During Bioactivation 54
  • 55. Sites for Carcinogen-DNA Adducts I O 6 N HN 5 7 1 8 II 2 4 9 3 III H2N N N I. Alkylating Agents, Mycotoxins DNA II. Aromatic Amines III. Polycyclic Aromatic Hydrocarbons, Alkenylbenzenes 55
  • 56. Examples of Carcinogen-DNA Adducts 56
  • 57. Examples of DNA DamageBreak – single strand – double StrandCrosslink – DNA-protein – intra-protein – intra-strandSpecific bindingBase alterationBase detachmentIntercolation 57
  • 58. DNA Repair Processes Direct damage reversal – Ex.: Alkyltransferases Base excision repair – Ex.: Glycosylases and apurinic/apyrimidinic – EndonucleasesSource Pitot & Dragan. In Casarett & Doull, 1996 Continued 58
  • 59. DNA Repair Processes Nucleotide excision repair – Ex.: repair of pyrimidine dimers – Repair of “bulky” adducts Recombination: Postreplication repair Mismatch repair – Ex.: Repair of deaminated 5- methylcytosineSource Pitot & Dragan. In Casarett & Doull, 1996 59
  • 60. 60
  • 61. 61
  • 62. GenotoxicityMutagenesis– Occurrence of “point” or “gene-locus” mutation (base pairs), substitution, and small deletions or additionsClastogenesis– Occurrence of chromosomal breaks resulting in gain, loss, or rearrangement of pieces of chromosome Continued 62
  • 63. GenotoxicityAneuplodization– Gain or loss of one or more chromosomes 63
  • 64. Genetic Damage and CancerGain of function: (proto-oncogenes andoncogenes) – Point mutation – Translocation – AmplificationLoss of function: (tumor suppressor genes) – Deletion – Translocation – Mutation 64
  • 65. Ways By Which Different Oncogene ProductsMay Disrupt Normal Regulation of Cell Growth Growth Factors Receptors 2nd Messengers DNA Synthesis Oncogenes 65
  • 66. Functions of Representative Oncogenes and Tumor Suppressor Genes A. OncogenesFunctions of Gene Product Genes Cell LocalizationGrowth 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 Continued 66
  • 67. Functions of Representative Oncogenes and Tumor Suppressor Genes B. Tumor Suppressor genesFunctions of Gene Product Genes Cell LocalizationGTPase activation NF1 Cell membrane/cytoplasmicCell cycle-regulated nuclear transcriptional repressor RB-1 NuclearCell cycle-regulated nuclear transcription factor p53 NuclearZinc finger transcription factor WT1 NuclearMismatch DNA repair hMLH1 NuclearZinc finger transcription factor (?) BRCA1 Nuclear 67
  • 68. Role of Estrogen in Mammary Carcinogenesis 68
  • 69. Section DMultistage Nature of Carcinogenesis II
  • 70. Multistage Carcinogenesis 70
  • 71. Mechanisms of Chemical CarcinogenesisActivation of carcinogens bybiotransformationMultistage carcinogenesis – Initiation: somatic cell mutation – Promotion: clonal expansion of initiated cells – Progression: evolution of neoplastic phenotype (angiogenesis, invasiveness, metastasis) 71
  • 72. Initiation and Promotion Operational Definitions Initiator NoTumors Promotor ManyTumors 72
  • 73. Mechanisms for Selectionand Clonal Expansion by Tumor Promoters 73
  • 74. Chemical Structures of Some Tumor Promoters 74
  • 75. Promoters Can Determine the Target Site for Tumors Initiator Tumor Promoter Target Organ2-AAF or BBN phenobarbital liver saccharin bladderN-methylnitroso- phenobarbital liver & thyroidurea saccharin bladder 75
  • 76. Neoplasms Associated with Prolonged Contact With Promoting Agents in the EnvironmentAgent 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 76
  • 77. Lung CancerSince 1987, more women have died of lungcancer than breast cancerRisk factors: SMOKING, industrialexposures, radiation exposureEarly detection: DifficultPrevention: STOP SMOKING! 77
  • 78. Smoking and Lung Cancer 78
  • 79. Relative Risk for Developing Lung Cancer Compared with the Risk of Dying from Lung Cancer for a Nonsmoker not Exposed to Asbestos Nonsmoking asbestos worker 5 Smokers not exposed to asbestos 11 Smoking asbestos workers 53 Asbestos workers smoking 1 87 pack/day 0 20 40 60 80 100 Times HigherSource: Report of the Surgeon General, 1985 79
  • 80. EFFECT OF SMOKING CESSATION ON MORTALITY FROM LUNG CANCER(former smoker/never smoker) 30 MORTALITY RATE RATIO 40+ # cigarettes per day 25 20 15 21-39 20 10 10-19 5 1-9 0 5 10 15 20 25 Duration of Cessation (years) 80
  • 81. Multistage Carcinogenesis 81
  • 82. Tumor ProgressionConversion of benign tumor to malignancyDNA-damaging agents are goodprogressors – Alkylating agents (mutagens) – H202 and organic peroxides – Radiation 82
  • 83. Malignant Conversion by Benzoyl Peroxide 83
  • 84. Morphological and Biological Characteristics of Initiation, Promotion, and Progression INITIATION PROMOTION PROGRESSIONIrreversible Operationally reversible Irreversible both at the level of gene expression and at the cellular levelInitiated “stem cell” not Promoted cell population Morphologicallymorphologically dependent on continued discernible alteration inidentifiable administration of cellular structure promoting agent resulting from karyotypic instabilityEfficiency sensitive to Efficiency sensitive to Growth of altered cellsxenobiotic and other aging and dietary and sensitive to environchemical factors hormonal factors mental factors during early phase of this stageSpontaneous Endogenous promoting(endogenous) agents may effectoccurrence of initiated “spontaneous”cells promotion Continued 84
  • 85. Morphological and Biological Characteristics of Initiation, Promotion, and Progression INITIATION PROMOTION PROGRESSIONRequirement for celldivision for “fixation”Dose-response not Dose response exhibits Benign or malignantexhibiting a readily measurable threshold neoplasms observed inmeasurable threshold and maximal effect this stageRelative potency of Relative potency of “Progressor” agentsinitiators dependent on promoters measured by advance promoted cellsquantitation of their effectiveness in into this stagepreneoplastic lesions causing an expansion ofafter defined period of the initiated cellpromotion population 85
  • 86. Some Cellular and Molecular Mechanisms in Multistage Carcinogenesis INITIATION PROMOTION PROGRESSIONSimple mutations Reversible enhancement Complex genetic(transitions or repression of gene alterationstransversions, small expression mediated via (chromosomaldeletions, etc.) involving receptors specific for the translocations, deletions,the cellular genome individual promoting gene amplification, agent recombination, etc.) resulting from evolving karyotypic instabilityIn some species and Inhibition of apoptosis Irreversible changes intissues point mutations by promoting agent; gene expression,in protooncogenes selective cytotoxicity to including fetal geneand/or oncogenes non-initiated cells expression, altered major histocompatibility complex (MHC) gene expression, and ectopic hormone production Continued 86
  • 87. Some Cellular and Molecular Mechanisms in Multistage Carcinogenesis INITIATION PROMOTION PROGRESSIONMutations in genes of No direct structural Selection of neoplasticsignal transduction alteration in DNA from cells for optimal growthpathways that may action or metabolism of genotype phenotype inresult in an altered promoting agent response to the cellularphenotype environment and including the evolution of karyotypic instability 87
  • 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 cells Promoting agent: A chemical capable of causing the expansion of initiated cell clones Continued 88
  • 89. Classification of Chemical Carcinogens In Relation to Their Action on One or More Stages of Carcinogenesis Progressor agent: A chemical capable of converting an initiated cell or a cell in the stage of promotion to a potentially malignant cell Continued 89
  • 90. Classification of Chemical Carcinogens In Relation to Their Action on One or More Stages of Carcinogenesis Complete carcinogen: A chemical possessing the ability to induce cancer from normal cells, usually with properties of initiating, promoting, and progressor agents 90
  • 91. Prevention of CarcinogenesisAffordable cancer = Prevention +Protection 91
  • 92. PreventionElimination of carcinogenic influences(e.g., industrial carcinogens, cigarettesmoking, radiation – Knowledge of identity of carcinogen is essential 92
  • 93. ProtectionMeasures designed to interrupt thecarcinogenic process without specificefforts to identify or eliminate carcinogenicinfluences (e.g., dietary measures) – Knowledge of identity of carcinogen is desirable 93
  • 94. Key PointsEnvironmental factors may contribute to3/4 of all human cancersChemicals, viruses, and radiation can becarcinogenicDNA is a major target for carcinogens – With damage leading to gain or loss of function of key genes Continued 94
  • 95. Key PointsCarcinogenesis is a long, multistageprocess yielding a heterogeneous family ofdiseases: CancerMost cancer is, in theory, preventable 95