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) 1O •OH O•2 – H2O2 2 Reactive Nitrogen Species (RNS) NO ONOO N2O3– Protein Damage (DNA Repair Enzymes, Caspases) DNA Damage and Mutation Nitrosamines/Deamination 8-oxo-dG 8-nitroguanine Etheno Adducts M1G Adduct S-nitrosothiol SSB’s DSB’s NFB AP-1 Lipid Peroxidation Arachidonic Acid Cascade MDA Eicosanoids Cell Proliferation Survival (malondialdehyde) 4HNE (4-hydroxynonenal) Cancer 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 Infections & Chronic Inflammation Environmental Factors Diet Occupational Factors Oxidative Stress Cancer 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  Prooxidant Nitric Oxide Synthase-2  Antioxidant  A prooxidant state is common in human cancer  Most cancers poorly metabolize hydrogen peroxide Oberley & Oberley, Histol Histopathol 1997 A MnSOD Gene Polymorphism Modulates Breast Cancer Survival Kaplan-Meier Survival Analysis 1.00 Val/Val Val/Ala 0.75 0.50 0.25 0 0 Log-rank Test P<0.005 Ala/Ala 1000 2000 3000 4000 Survival Time (Days) CANCER CAUSES Cause % of all cancers 30-35 15-30 10-20 < 10 <5 Nutrition Tobacco Chronic Infections High Penetrance Genes Any Other Individual Cause 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) INTAKE OF FRUIT AND VEGETABLES AND CANCER RISK Cancer All Sites Lung Larynx Oral, pharynx Esophagus Stomach Colorectal Bladder Pancreas Cervix Ovary Breast Prostate No. of Studies 170 25 4 9 16 19 27 5 11 8 4 14 14 Protective 132 24 4 9 15 17 20 3 9 7 3 8 4 Harmful 6 0 0 0 0 1 3 0 0 0 0 0 2 RR (95% CI) low vs. high intake 2.2 (1.2-7.0) 2.3 (2.1-2.8) 2.0 (1.7-2.5) 2.5 (0.5-5.8) 1.9 (0.7-4.8) 2.5 (0.5-5.8) 1.9 (0.3-3.3) 2.1 (1.6-2.1) 2.8 (1.4-6.4) 2.0 (1.2-6.4) 1.8 (1.1-2.3) 1.3 (1.1-2.8) 1.3 (0.6-3.5) Block et al., Nutr Cancer 1992 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 AGE-ADJUSTED PREVALENCE OF OBESITY FOR ADULTS IN THE UNITED STATES, 1960-2000 35 Prevalence of Obesity (%) 30 25 20 15 10 5 0 MEN WOMEN Calle and Thun, Oncogene 2004 1960-62 1971-74 1976-80 1988-94 1999-00 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 OVERWEIGHT AND OBESITY ACCOUNT FOR 10% to 20% OF CANCER DEATHS IN THE US Women RR§ 1.44 1.46 1.51 1.68 1.88 1.95 Men RR 1.34 1.49 1.52 1.70 1.71 1.76 1.84 1.91 1.94 2.61 4.52 • • • • • • • • • • • • • Multiple Myeloma Colorectal Ovarian Liver All Cancers Non-Hodgkin’s lymphoma Breast Gall Bladder Esophagus Pancreas Cervix Kidney Uterus • Prostate • Non-Hodgkin’s • • • • • • • • • lymphoma All Cancers Kidney Multiple Myeloma Gall Bladder Colorectal Esophagus Stomach Pancreas Liver 2.12 2.13 2.64 2.76 3.20 4.75 6.25 § Calle and Thun, Oncogene 2004; RR Mortality comparing BMI 30-40 versus 18.5-24.9 EVIDENCE FOR ROS & RNS IN CANCER ETIOLOGY • • • • • • • • • • Lung Liver Stomach Bladder Colorectal Esophageal Prostate Leukemia Skin Kidney Loft & Poulsen, J Mol Med 1996 NON-STEROIDAL ANTI-INFLAMMATORY DRUGS REDUCE COLON CANCER RISK Summary of Cohort Studies Thun et al., JNCI 2002 NON-STEROIDAL ANTI-INFLAMMATORY DRUGS REDUCE HUMAN CANCER RISK Cancer Site Esophagus Stomach Lung Breast Prostate advanced disease Ovary Bladder § NSAIDs Use Aspirin Use § Relative Risk (95% CI) Relative Risk (95% CI) 0.65 (0.46-0.92) 0.57 (0.44-0.74) 0.65 (0.34-1.22) 0.77 (0.66-0.88) 0.67 (0.37-1.22) 0.74 (0.61-0.90) 0.91 (0.71-1.18) 0.51 (0.38-0.69) 0.73 (0.63-0.86) 0.84 (0.66-1.07) 0.77 (0.69-0.86) 0.90 (0.82-0.99) 0.70 (0.52-0.94) 0.91 (0.79-1.06) 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 INFECTIOUS AGENTS AND CANCER • Viruses cause about 10%-15% of all cancers worldwide • Bacteria about 5% • Parasites less than 1% IARC Data CANCER CASES WORLDWIDE CANCER CASES PER YEAR • HUMAN PAPILLOMA VIRUS • HELIOBACTER PYLORI • HEPATITIS B & C • EPSTEIN-BARR VIRUS • HUMAN HERPES VIRUS 8 • T-CELL LYMPHOTROPIC VIRUS • SCHISTOSOMA HAEMATOBIUM • OPISTHORCHIS VIVERRINI IARC, 2003 550,000 490,000 390,000 99,000 54,000 2,700 9,000 800 CANCER CAUSES Cause % of all cancers 30-35 15-30 10-20 < 10 <5 Nutrition Tobacco Chronic Infections High Penetrance Genes Any Other Individual Cause 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 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 • UVA radiation (320 - 400 nm) leads to oxidation reactions • Cellular photosensitizers generate 1O2 and O• – 2 • UVA photons penetrate deeper into the epidermis layer than the higher-energetic UVB radiation • CC  TT transitions is the molecular signature of sunlight exposure 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 SUMMARY 1. Oxidative stress is involved in human cancer causation and promotes disease progression 2. Knowledge of tumor redox biology promises better prevention strategies and new treatment options Program in Molecular Epidemiology of Breast and Prostate Cancer Breast and Prostate Unit Brenda Boersma Tiffany Howe Robyn Prueitt Collaborators Julie Goodman Stephen Chanock