OXIDATIVE STRESS IN CANCER EPIDEMIOLOGY

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OXIDATIVE STRESS IN CANCER EPIDEMIOLOGY
Stefan Ambs Laboratory of Human
Carcinogenesis National Cancer Institute
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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 E
theno Adducts M1G Adduct S-nitrosothiol SSBs DSB
s
Eicosanoids
MDA (malondialdehyde) 4HNE (4-hydroxynonenal)
Cell Proliferation
Cancer
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OXIDATIVE STRESS PREDISPOSES TO CANCER

• Viral Hepatitis
• Ulcerative Colitis
• Chronic Bronchitis
• Chronic Gastritis
• Chronic Pancreatitis
• Barretts Esophagus
• Wilsons Disease
• Hemochromatosis

Hussain et al, Nat Rev Cancer 2003
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Oxidative Stress
Infections Chronic Inflammation
Environmental Factors
Occupational Factors
Diet
Cancer
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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
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A MnSOD Gene Polymorphism Modulates Breast Cancer
Survival
Kaplan-Meier Survival Analysis
1.00
Val/Val
0.75
Val/Ala
Log-rank Test P0.50
Ala/Ala
0.25
0
0
1000
2000
3000
4000
Survival Time (Days)
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CANCER CAUSES

• Cause of all cancers
• Nutrition 30-35
• Tobacco 15-30
• Chronic Infections 10-20
• High Penetrance Genes
• Any Other Individual Cause

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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)

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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
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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
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AGE-ADJUSTED PREVALENCE OF OBESITY FOR ADULTS IN
THE UNITED STATES, 1960-2000
Prevalence of Obesity ()
Calle and Thun, Oncogene 2004
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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
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OVERWEIGHT AND OBESITY ACCOUNT FOR 10 to 20 OF
CANCER DEATHS IN THE US

• Men RR
• Prostate 1.34
• Non-Hodgkins 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

• Women RR
• Multiple Myeloma 1.44
• Colorectal 1.46
• Ovarian 1.51
• Liver 1.68
• All Cancers 1.88
• Non-Hodgkins 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

Calle and Thun, Oncogene 2004 RRMortality
comparing BMI 30-40 versus 18.5-24.9
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EVIDENCE FOR ROS RNS IN CANCER ETIOLOGY

• Lung
• Liver
• Stomach
• Bladder
• Colorectal
• Esophageal
• Prostate
• Leukemia
• Skin
• Kidney

Loft Poulsen, J Mol Med 1996
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NON-STEROIDAL ANTI-INFLAMMATORY DRUGS REDUCE
COLON CANCER RISK
Summary of Cohort Studies
Thun et al., JNCI 2002
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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
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INFECTIOUS AGENTS AND CANCER

• Viruses cause about 10-15 of all cancers
  worldwide
• Bacteria about 5
• Parasites less than 1

IARC Data
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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
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CANCER CAUSES

• Cause of all cancers
• Nutrition 30-35
• Tobacco 15-30
• Chronic Infections 10-20
• High Penetrance Genes
• Any Other Individual Cause

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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
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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 generate 1O2 and O2
• UVA photons penetrate deeper into the epidermis
  layer than the
• higher-energetic UVB radiation

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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
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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

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