RELATIVE CONTRIBUTION OF OXIDATIVE STRESS TO HUMAN CANCER: EVIDENCE FROM CANCER EPIDEMIOLOGY Stefan Ambs, Ph.D. Laboratory of Human Carcinogenesis National Cancer Institute

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RELATIVE CONTRIBUTION OF OXIDATIVE STRESS TO
HUMAN CANCER EVIDENCE FROM CANCER EPIDEMIOLOGY
Stefan Ambs,
Ph.D.Laboratory of Human CarcinogenesisNational
Cancer Institute
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The Hallmarks of Cancer
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MECHANISMS LEADING TO OXIDATIVE STRESS
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EXPRESSION OF ANTIOXIDANT AND PROOXIDANT ENZYMES
CHANGES IN CANCER

• Manganese Superoxide Dismutase
• ? many cancers
• candidate tumor suppressor gene
• Cu/Zn Superoxide Dismutase ?
• Catalase ?
• Glutathione Peroxidase-1 ?
• Cyclooxygenase-2, Lipoxygenases ?
• Nitric Oxide Synthase-2 ?
• A prooxidant state is common in cancer cells
• Many cancers poorly metabolize hydrogen peroxide
• H2O2 concentration is commonly increased
  in human tumor cells

Antioxidant
Prooxidant
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Different Research Approaches to the Same
Question
Observational Research,
Intervention Trial, Molecular and Cellular
Research, Nutrition Research, Animal
StudiesOxidative Stress

Exposure to reactive oxygen (ROS) and
nitrogen (RNS) species
Cancer
OnsetProgression
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Infections Chronic Inflammation
Environmental
Occupational Factors
Factors
Diet Oxidative Stress, which
leads to cancer, is influenced by diet,
environmental factors, infections, occupational
factors. Cancer
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PROOXIDANT STATE BY INHERITED PREDISPOSITION.
Are there individuals
with an inherited pro-oxidant state who have an
increased risk of developing an illness like
cancer? High risk Wilsons disease and
hemochromatosis.Low risk Defense genes such as
SOD2(Val16Ala) or NQO1 (Pro187Ser)
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MnSOD Val16Ala GENOTYPE MODULATES BREAST CANCER
SURVIVAL After 11 years only 50 of the patients
with the Ala/Ala MnSOD genotype survive, whereas
60 survive with the Val/Ala genotype and 90
survive with the Val/Val genotype.
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CANCER CAUSES WORLDWIDE

• Cause of all cancers
• Nutrition 30-35
• Tobacco 15-30
• Chronic Infections 10-20
• High Penetrance Genes lt 10
• Any Other Individual Cause lt 5

The International Agency for Research on Cancer
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WESTERN STYLE DIET INDUCES OXIDATIVE STRESS

• A diet high in fat and low in calcium vitamin D
  induced changes in the colon of mice consistent
  with pro-oxidant redox changes in colon
  epithelial cells and a pro-inflammatory response
  by the organ

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NUTRITION AND CANCER

• Evidence
• Migration Studies
• Association Studies
• Intervention Trials
• A high intake of fruits, vegetables, tea, fish
  oil and selenium is associated with low risk.
• A high intake of alcohol, red meat, animal fat,
  salted fish, charbroiled foods, salt-preserved
  foods, and contaminated foods is associated with
  high risk.

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COMMON DESIGNS IN EPIDEMIOLOGICAL STUDIES

• Case Control study
• Recruits cases and controls at the same time
• Previous exposures (e.g., diet) are assessed with
  questionnaire
• Investigates the frequency of exposure among
  cases and controls (retrospective assessment of
  exposure)
• Prospective study
• Disease-free participants with known exposure are
  followed-up to assess the relationship between
  disease development and exposure

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TOMATO-BASED PRODUCTS AN CANCER RISK. Raw
tomatoes decreased the relative risk of getting
prostate cancer to 0.89 whereas cooked products
decreased the relative risk to 0.81.

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FDAS EVIDENCE-BASED REVIEW OF HEALTH CLAIMS FOR
TOMATOES AND LYCOPENE

• Review to make Qualified Health Claims
  requested by Lycopene Health Claim Coalition
  (Heinz Company, LycoRed Natural Products
  Industries, The Prostate Cancer Foundation) and
  American Longevity, Inc.
• FDA found very limited evidence to support an
  association between tomato consumption and
  reduced risks of prostate, ovarian, gastric, and
  pancreatic cancers
• Preliminary scientific research suggests eating
  one-half to one cup of tomatoes and tomato sauce
  a week may reduce the risk of prostate cancer
• No credible evidence for lung, colorectal,
  breast, cervical, or endometrial cancer

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MORE RECENT RESULTS FROM OBSERVATIONAL STUDIES

• Vitamin A, C, E, and folate, and lung cancer
  risk Pooled analysis of 8 prospective studies
  (Int J Cancer 2006)
• Data do not support the hypothesis that intakes
  of these vitamins and folate reduce lung cancer
  risk
• Fruit, vegetables and prostate cancer risk
  Results from the multiethnic cohort study (Cancer
  Causes Control 2006)
• No significant associations intake of tomato
  products is associated with a modest increase of
  risk (ptrend is .0001)
• Regular multivitamin use and prostate cancer
  (JNCI 2007)
• No association with localized cancer increased
  risk of advanced disease (excessive use)
• Dietary fibers and colorectal cancer risk Pooled
  analysis of 13 prospective studies (JAMA 2005)
• Data do not support the hypothesis that high
  fiber intake reduces colorectal cancer risk

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AGE-ADJUSTED PREVALENCE OF OBESITY FOR ADULTS IN
THE UNITED STATES, 1960-2000 In 1960 11 of the
men and 15 of the women were obese. In 1970 12
of the men and 16 of the women were obese. In
1980 13 of the men and 17 of the women were
obese In 1990 21 of the men and 27 of the
women were obese In 2000 29 of the men and 34
of the women were obese
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OVERWEIGHT AND OBESITY MAY 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

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INCREASED MORTALITY WITH HIGH BODY MASS INDEX
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EVIDENCE FOR ROS RNS IN CANCER ETIOLOGY

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

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NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDS)
AND COLON CANCER RISK
Summary of Prospective Studies
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ASPIRIN REDUCES RISK OF CANCER DEATHS
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CANCER CAUSES

• Cause of all cancers
• Nutrition 30-35
• Tobacco 15-30
• Chronic Infections 10-20
• High Penetrance Genes lt 10
• Any Other Individual Cause lt 5

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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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LUNG CANCER PREVENTION TRIALS

• Alpha-tocopherol Beta-carotene Trial (ATBC,
  Finland)
• Carotenoid and Retinol Efficacy Trial (CARET, US)
• Physicians Health Study (PHS, US)
• Womens Health Study (WHS, US)

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PREVENTION TRIAL RESULTS
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CONCLUSION FROM TRIALS

• Pharmaceutical doses of antioxidants that
  apparently are nontoxic bioactive compounds in
  the general population may have adverse effects
  in individuals with high-risk behavior such as
  high smoking and alcohol intake

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CANCER CAUSES

• Cause of all cancers
• Nutrition 30-35
• Tobacco 15-30
• Chronic Infections 10-20
• High Penetrance Genes lt 10
• Any Other Individual Cause lt 5

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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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INFECTIONS ASSOCIATED WITH HUMAN CANCER

• Virus
• Hepatitis B C Virus cause liver cancer
• Human Papilloma Virus causes cervical cancer
• Epstein-Barr Virus causes Burkitts lymphoma
• Human T-Cell Lymphotropic Virus causes Adult
  T-cell leukemia
• HIV HHV-8 cause Kaposis sarcoma
• Helicobacter pylori causes gastric cancer
• Schistosomes cause bladder cancer
• Liver fluke causes cholangiosarcomas

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CANCER CAUSES

• Cause of all cancers
• Nutrition 30-35
• Tobacco 15-30
• Chronic Infections 10-20
• High Penetrance Genes lt 10
• Any Other Individual Cause lt 5

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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

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Oxidative stress and cancer progression.
?Glucose deprivation, metabolic alterations,
growth factor signaling, monocyte infiltration
and exposure to heavy metals leads to oxidative
stress. ? Poor blood supply and high energy use
lead to hypoxia. ?Oxidative stress and hypoxia
lead to genomic instaiblity, cell mobility,
exgtracellular matrix and angiogenesis.
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NF-?B IN CANCER PROGRESSION

• NF-?B pathway activation is frequently observed
  in metastatic human tumors
• NF-?B knockout inhibits metastasis in a murine
  models of lung, liver and prostate cancer
• Activators of NF-kB pathway
• Environmental hazards (metals, smoking)
• Infections
• Physiological stress
• Inflammation

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SUMMARY ? There is strong evidence that
oxidative stress is involved in human cancer
causation and promotes disease progression?Cance
r epidemiology has not succeeded in linking
specific antioxidants to a reduced cancer
burden?Knowledge of tumor redox biology
promises better prevention strategies and new
treatment options