# Presentation: 275176

## OXIDATIVE STRESS IN CANCER EPIDEMIOLOGY

**Stefan Ambs**
**Laboratory of Human Carcinogenesis**
**National Cancer Institute**

## Cancer

**OXIDATIVE STRESS: EXCESS OF FREE RADICALS**** **

**Reactive Oxygen Species (ROS)**
**      ****1****O****2****      •****OH      O****2        ****H****2****O****2**

**Reactive Nitrogen Species (RNS)**
**      ****NO     ONOO      N****2****O****3**

**MDA**
**(malondialdehyde)**
**4HNE**
**(4-hydroxynonenal)**

**DNA Damage**
**and Mutation**

**Nitrosamines/Deamination**
**8-oxo-dG**
**8-nitroguanine**
**Etheno Adducts**
**M1G Adduct**
**S-nitrosothiol**
**SSB’s**
**DSB’s**

**Lipid **
**Peroxidation**

**Arachidonic Acid**
**Cascade**

**Eicosanoids**

**Cell **
**Proliferation**

**Protein Damage****  **
**(DNA Repair Enzymes, Caspases)**

- • –

- –

**Cancer**

**NF********B**
**AP-1**

**Survival**

## 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

## Oxidative Stress

**Cancer**

**Diet**

**Environmental **
**Factors**

**Occupational **
**Factors**

**Infections & Chronic Inflammation**

## 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

## A MnSOD Gene Polymorphism Modulates Breast Cancer Survival

**Kaplan-Meier Survival Analysis**

**Survival Time (Days)**

**0**

**1000**

**2000**

**3000**

**4000**

**0**

**0.25**

**0.50**

**0.75**

**1.00**

**Val/Val**

**Val/Ala**

**Ala/Ala**

**Log-rank Test**
-      P<0.005

## 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

## 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           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

## TOMATO-BASED PRODUCTS AND CANCER RISK

**Giovannucci, JNCI 1999**

**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*

## AGE-ADJUSTED PREVALENCE OF OBESITY FOR ADULTS IN THE UNITED STATES, 1960-2000

**Prevalence of Obesity (%)**

- Calle and Thun, Oncogene 2004

## COVERGENCE OF ADIPOCYTE AND MACROPHAGE FUNCTIONS IN OBESITY 

**Obesity and Chronic Inflammation**

**Adipocyte & Macrophage: Lipid storage ********, Cytokine ******

**Xu et al., J Clin Invest 2004**

**Increase of circulating**
**C-reactive protein**
- Indicates a persistent
- low-grade inflammation
- in adipose tissue in conditions of overweight & obesity

## OVERWEIGHT AND OBESITY ACCOUNT FOR 10% to 20% OF CANCER DEATHS IN THE US

- 	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

- 	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

- § 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****	****	****         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

## 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                           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

## 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

##  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
-  CC  TT transitions is the molecular signature of sunlight exposure
-  UVA radiation (320 - 400 nm) leads to oxidation reactions
-  Cellular photosensitizers generate** ****1****O****2**** **and **O****2**
-  UVA photons penetrate deeper into the epidermis layer than the
-    higher-energetic UVB radiation

- • –

## 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**
**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**