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OXIDATIVE STRESS IN CANCER EPIDEMIOLOGY

OXIDATIVE STRESS IN CANCER EPIDEMIOLOGY. Stefan Ambs Laboratory of Human Carcinogenesis National Cancer Institute. OXIDATIVE STRESS: EXCESS OF FREE RADICALS. Reactive Oxygen Species (ROS) 1 O 2 • OH O 2 H 2 O 2. Reactive Nitrogen Species (RNS)

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OXIDATIVE STRESS IN CANCER EPIDEMIOLOGY

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  1. OXIDATIVE STRESS IN CANCER EPIDEMIOLOGY Stefan Ambs Laboratory of Human Carcinogenesis National Cancer Institute

  2. OXIDATIVE STRESS: EXCESS OF FREE RADICALS Reactive Oxygen Species (ROS) 1O2 •OH O2 H2O2 Reactive Nitrogen Species (RNS) NO ONOO N2O3 • – – Protein Damage (DNA Repair Enzymes, Caspases) Lipid Peroxidation NFB AP-1 DNA Damage and Mutation Arachidonic Acid Cascade Survival Nitrosamines/Deamination 8-oxo-dG 8-nitroguanine Etheno Adducts M1G Adduct S-nitrosothiol SSB’s DSB’s Eicosanoids MDA (malondialdehyde) 4HNE (4-hydroxynonenal) Cell Proliferation Cancer

  3. OXIDATIVE STRESS PREDISPOSES TO CANCER • Viral Hepatitis • Ulcerative Colitis • Chronic Bronchitis • Chronic Gastritis • Chronic Pancreatitis • Barrett’s Esophagus • Wilson’s Disease • Hemochromatosis Hussain et al, Nat Rev Cancer 2003

  4. Infections & Chronic Inflammation Oxidative Stress Occupational Factors Environmental Factors Diet Cancer

  5. EXPRESSION OF ANTIOXIDANT AND PROOXIDANT ENZYMES CHANGES IN CANCER • Manganese Superoxide Dismutase • in most cancers • Candidate Tumor Suppressor Gene • Cu/Zn Superoxide Dismutase  • Catalase  • Glutathione Peroxidase-1  • Cyclooxygenase-2  • Nitric Oxide Synthase-2  • A prooxidant state is common in human cancer • Most cancers poorly metabolize hydrogen peroxide Antioxidant Prooxidant Oberley & Oberley, Histol Histopathol 1997

  6. A MnSOD Gene Polymorphism Modulates Breast Cancer Survival Kaplan-Meier Survival Analysis 1.00 Val/Val 0.75 Val/Ala Log-rank Test P<0.005 0.50 Ala/Ala 0.25 0 0 1000 2000 3000 4000 Survival Time (Days)

  7. CANCER CAUSES Cause % of all cancers Nutrition 30-35 Tobacco 15-30 Chronic Infections 10-20 High Penetrance Genes < 10 Any Other Individual Cause < 5

  8. NUTRITION AND CANCER Evidence • Migration Studies • Association Studies • Intervention Trials • High Intake = Low Risk • Fruit • Vegetables • Tea Components • Polyunsaturated Fats • Dietary Fish Oil • Selenium • High Intake = High Risk • Alcohol • Red Meat Intake • Animal Fat • Salted Fish • Charbroiled Foods • Salt-preserved Foods • Contaminated Foods (Fungus)

  9. INTAKE OF FRUIT AND VEGETABLES AND CANCER RISK Cancer No. of Studies Protective Harmful RR (95% CI) low vs. high intake All Sites 170 132 6 2.2 (1.2-7.0) Lung 25 24 0 2.3 (2.1-2.8) Larynx 4 4 0 2.0 (1.7-2.5) Oral, pharynx 9 9 0 2.5 (0.5-5.8) Esophagus 16 15 0 1.9 (0.7-4.8) Stomach 19 17 1 2.5 (0.5-5.8) Colorectal 27 20 3 1.9 (0.3-3.3) Bladder 5 3 0 2.1 (1.6-2.1) Pancreas 11 9 0 2.8 (1.4-6.4) Cervix 8 7 0 2.0 (1.2-6.4) Ovary 4 3 0 1.8 (1.1-2.3) Breast 14 8 0 1.3 (1.1-2.8) Prostate 14 4 2 1.3 (0.6-3.5) Block et al., Nutr Cancer 1992

  10. TOMATO-BASED PRODUCTS AND CANCER RISK • Tomato Sauce-based Pasta Dish • 8-OH-dG in Leukocytes  20% • 8-OH-dG in Prostate  28% • Chen et al., JNCI 2001 Prostate Cancer & Tomato Products Raw tomatoes: RR = 0.89 (0.8-1.0) Cooked Products: RR = 0.81 (0.71-0.92) Etminan et al., CEBP 2004 Giovannucci, JNCI 1999

  11. AGE-ADJUSTED PREVALENCE OF OBESITY FOR ADULTS IN THE UNITED STATES, 1960-2000 Prevalence of Obesity (%) Calle and Thun, Oncogene 2004

  12. COVERGENCE OF ADIPOCYTE AND MACROPHAGE FUNCTIONS IN OBESITY Obesity and Chronic Inflammation Adipocyte & Macrophage: Lipid storage , Cytokine  Increase of circulating C-reactive protein Indicates a persistent low-grade inflammation in adipose tissue in conditions of overweight & obesity Xu et al., J Clin Invest 2004

  13. OVERWEIGHT AND OBESITY ACCOUNT FOR 10% to 20% OF CANCER DEATHS IN THE US • Women RR§ • Multiple Myeloma 1.44 • Colorectal 1.46 • Ovarian 1.51 • Liver 1.68 • All Cancers 1.88 • Non-Hodgkin’s 1.95 • lymphoma • Breast 2.12 • Gall Bladder 2.13 • Esophagus 2.64 • Pancreas 2.76 • Cervix 3.20 • Kidney 4.75 • Uterus 6.25 Men RR • Prostate 1.34 • Non-Hodgkin’s 1.49 lymphoma • All Cancers 1.52 • Kidney 1.70 • Multiple Myeloma 1.71 • Gall Bladder 1.76 • Colorectal 1.84 • Esophagus 1.91 • Stomach 1.94 • Pancreas 2.61 • Liver 4.52 § Calle and Thun, Oncogene 2004; RRMortality comparing BMI 30-40 versus 18.5-24.9

  14. EVIDENCE FOR ROS & RNS IN CANCER ETIOLOGY • Lung • Liver • Stomach • Bladder • Colorectal • Esophageal • Prostate • Leukemia • Skin • Kidney Loft & Poulsen, J Mol Med 1996

  15. NON-STEROIDAL ANTI-INFLAMMATORY DRUGS REDUCE COLON CANCER RISK Summary of Cohort Studies Thun et al., JNCI 2002

  16. NON-STEROIDAL ANTI-INFLAMMATORY DRUGS REDUCE HUMAN CANCER RISK Cancer Site NSAIDs Use Aspirin Use Relative Risk (95% CI) § Relative Risk (95% CI) Esophagus 0.65 (0.46-0.92) 0.51 (0.38-0.69) Stomach 0.57 (0.44-0.74) 0.73 (0.63-0.86) Lung 0.65 (0.34-1.22) 0.84 (0.66-1.07) Breast 0.77 (0.66-0.88) 0.77 (0.69-0.86) Prostate 0.67 (0.37-1.22) 0.90 (0.82-0.99) advanced disease 0.70 (0.52-0.94) Ovary 0.74 (0.61-0.90) 0.91 (0.79-1.06) Bladder 0.91 (0.71-1.18) 0.91 (0.73-1.13) § versus non-users Gonzalez-Perez et al., BMC Cancer 2003; Mahmud et al., Br J Cancer 2004; Wang et al., JNCI 2003

  17. INFECTIOUS AGENTS AND CANCER • Viruses cause about 10%-15% of all cancers worldwide • Bacteria about 5% • Parasites less than 1% IARC Data

  18. CANCER CASES WORLDWIDE CANCER CASES PER YEAR • HUMAN PAPILLOMA VIRUS 550,000 • HELIOBACTER PYLORI 490,000 • HEPATITIS B & C 390,000 • EPSTEIN-BARR VIRUS 99,000 • HUMAN HERPES VIRUS 8 54,000 • T-CELL LYMPHOTROPIC VIRUS 2,700 • SCHISTOSOMA HAEMATOBIUM 9,000 • OPISTHORCHIS VIVERRINI 800 IARC, 2003

  19. CANCER CAUSES Cause % of all cancers Nutrition 30-35 Tobacco 15-30 Chronic Infections 10-20 High Penetrance Genes < 10 Any Other Individual Cause < 5

  20. ROS & RNS IN LUNG CANCER ETIOLOGY • Tobacco Smoke • Increases urinary 8-oxodG excretion by 30%-50% • Contains ROS and ROS-generating compounds • Induces monocyte recruitment and activation (ROS & RNS ) • Induces CYP450 and ROS as a byproduct of CYP450 metabolism • Asbestos/Silicosis  5,000-10,000 cases per year in the US • Persistent inflammation • Generation of radicals at particle surface and by particle-activated cells • Radon 15,000 cases per year in the US • Decays by alpha particle emission (H20  HO• + H•) • Asthma and Chronic Bronchitis • Asthma: OR 1.8 (95% CI 1.3 - 2.6) • Bronchitis: OR 1.7 (95% CI 1.1 - 2.7) independent of smoking

  21. SKIN CANCER Skin Cancer Cases in the US (2002) • Basal Cell Carcinoma 900,000 • Squamous Cell Carcinoma 300,000 • Melanoma 54,000 • Major Cause: Sunlight • UVB radiation (290 - 320 nm) leads to DNA photoadducts • CC  TT transitions is the molecular signature of sunlight exposure • UVA radiation (320 - 400 nm) leads to oxidation reactions • Cellular photosensitizers generate1O2and O2 • UVA photons penetrate deeper into the epidermis layer than the • higher-energetic UVB radiation • –

  22. OXIDATIVE STRESS AND SKIN CANCER • UV radiation reduces activity of SOD and catalase • Tumor promoters in skin carcinogenesis • Active agents down regulate SOD and catalase • Phorbol esters that do not stimulate superoxide production are inactive in tumor promotion Slaga, Crit Rev Food Sci Nutr 1995

  23. SUMMARY • 1. Oxidative stress is involved in human cancer causation and promotes disease progression • Knowledge of tumor redox biology promises better prevention strategies and new treatment options

  24. Program in Molecular Epidemiology of Breast and Prostate Cancer Breast and Prostate Unit Brenda Boersma Tiffany Howe Robyn Prueitt Collaborators Julie Goodman Stephen Chanock

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