Nutrition and Cancer Prevention: What Do We Know? What Can You Do?
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1 Nutrition and Cancer Prevention: What Do We Know? What Can You Do? Stephen D. Hursting, PhD, MPH Professor, Nutrition Research Institute, Department of Nutrition and the Lineberger Comprehensive Cancer Center University of North Carolina
2 What is cancer? Today s Presentation Cancer prevention: Diet recommendations (focus on phytochemicals, obesity prevention) Examples of nutrition and cancer prevention research at the NRI
3 What is Cancer? Webster s: A malignant tumor of potentially unlimited growth that expands locally by invasion and systemically by metastasis. American Cancer Society: A group of diseases characterized by uncontrolled growth and spread of abnormal cells. If the spread is not controlled, it can result in death.
4 What is Cancer? The final stage of a multi-step process
5 Magnitude of the Cancer Problem in the World (Men and women Combined: 2014 estimates) #1 cause of death worldwide--over 8.3 million cancer deaths/year Over 14 million new cancer cases forecast to rise to ~25 million new cases by 2030 unless new preventive strategies are developed Global Cancer Report, IARC, 2014
6 Leading Causes of Death, All Races and Both Genders, U.S. (NCHS, CDC, U.S. Department of Health and Human Services, 2014) Rank Order and Number of Deaths ALL CAUSES 2,465,932 Diseases of the heart Malignant neoplasms (cancer) 596,577 (24% of deaths) 585,720 (23% of deaths) Chronic lower respiratory disease 137,789 Cerebrovascular disease (stroke) 129,180 Unintentional injuries (accidents) 118,043 Alzheimer s disease 83,308 Diabetes mellitus 68,905 Nephritis, nephrotic syndrome, and nephrosis 50,472 Pneumonia and influenza 50,003 Suicide 37,793 6 Lifetime risk of dying from cancer: 1 in 4
7 1940 s Advertisement from the United Kingdom
8 1940 s Advertisement Source: American from Cancer the Society, United Kingdom
9 Death Rates for All Cancers By Sex, Source: American Cancer Society, 2014.
10 5-Year Survival Rates for Major Cancers in US Organ If Localized If Metastasized Lung 49% 3% Colon 90% 10% Breast 98% 26% Prostate 100% 32% Pancreas 10% 1%
11 The Economic Costs of Cancer In the US in 2008: Cancer Treatment Costs: $104 billion (~5% of health care $) Cancer Morbidity: >$180 billion Worldwide in 2008: Cancer Treatment Costs: ~$850 billion Morbidity and Premature Mortality Costs: $895 billion (heart disease second at $753 billion) American Cancer Society,
12 Cancer: A Complex Foe The essential aberrations of cancer Altered Growth and Energetics Inflammation Evading death signals and immune surveillance Sustained angiogenesis Immortal; Limitless growth potential Genomic instability Tissue invasion and metastasis Adapted from: Hanahan & Weinberg, Cell (2011)
13 AICR/WCRF Expert Report Recommendations Continuous Update Program
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16 Ascorbic Acid Folate Polyphenolics Stanols & sterols Indole-3-carbinol Flavonoids Carotenoids Anthocyanidins Diets should contain a variety of plant-based foods WCRF/AICR 1997
17 Bioactive Food Components Influence Cancer Processes DNA Repair Carcinogen Metabolism Cell Cycle Bioactive Food Components Immune Function Hormonal Regulation Energy Metabolism
18 The Shape of Things to Come. The Economist 12/11/03. (
19 The US Obesity Epidemic No Data <10% 10% 14% Ogden, et al., JAMA 2014: 69% of US Adults Overweight or Obese (BMI >25.0 kg/m 2 ) 36% US Adults Obese (BMI >30.0 kg/m 2 ) 6.5% US Adults Extremely Obese (BMI >40.0 kg/m 2 )
20 Metabolic Syndrome Describes a state of metabolic dysregulation characterized by: Insulin resistance, hyperglycemia* Dyslipidemia ( triglycerides*, HDL-C*) Waist circumference* Hypertension* Proinflammatory state ( cytokines, chemokines) Vascular perturbations ( PAI-1, VEGF) Altered adipokines ( leptin, adiponectin) Elevated insulin-like growth factor (IGF)-1 Associated with many types of cancer 25% (144K) cancer deaths/year in US caused by overweight/obesity (Calle, et al., NEJM 2003; Colditz, et al. Science Transl Med, 2012)
21 % of cases of specific cancers caused by obesity: Endometrial: 49% Esophageal: 35% Pancreatic: 28% Kidney: 24% Gallbladder: 21% Breast: 19% Colorectal: 9% Total Cancers ~25% Source: American Institue for Cancer Research, 2014
22 Obesity: - a central challenge in cancer prevention and care - leading preventable cause. of cancer in US - can increase risk of cancer recurrence, lower survival - by 2030, ~500,000 Americans/yr diagnosed with obesity-related cancer unless corrective action
23 LOOMING QUESTION: How to Decrease Cancer Risk in the ~720 Million Adults Worldwide Currently Obese? Will Warfarin Still be in U a Year from Now? Need a mechanistic approach to identify targets and strategies to break obesity-cancer links
24 Obesity and Cancer: Emerging Mechanisms Mechanisms Underlying the Obesity-Cancer Link: 2013? Microenvironment (EMT, CSCs) S. Hursting and M. Hursting. Arterioscler Thromb Vasc Biol, 2012
25 Modeling Energy Balance and Human Cancer in Mice by Altering Key Genes and Pathways Insert fig Hursting, et al., Mutation Res, 2005
26 Molecular Profiling of Wnt-1 Tumors Relative to Well-Characterized Human and Murine Mammary Tumors Dr. Sarah Dunlap Cancer Prev Res, 2012
27 Energy Balance and Cancer Prevention Energy in Amount Type Pattern Energy Balance: kcal in = kcal out Energy out Physical Activity Routine Metabolism Thermoregulation Growth Storage
28 Calorie Restriction (~20% Reduction in Energy) Extends Lifespan in Multiple Species Yeast (S. cerevisiae) Worm (C. elegans)) Fly (D. melanogaster) Bowl and Doily Spider Labrador Retriever Hereford Cow % Increase in Longevity (versus ad libitum-fed controls) Hursting, et al. J Nutr, 2004
29 Control? Calorie Restricted 8.5 yrs. 9.0 yrs. Feb NCI, yrs 27.8 yrs yrs. July 2003 U of Texas, 2005 UNC, Age: years 55.7 yrs Weindruch: CR Study in Rhesus Monkeys (Colman, et al., Science 2009)
30 Growth Factor Levels and Wnt-1 Mammary Tumor Growth in Lean, Overweight and Obese Mice CR (30%) (29% body fat) n=12 mice/group IGF-1 Insulin Leptin Adiponectin L/A Tumor Vol (ng/ml) (pg/ml) (ng/ml) (ng/ml) (mm 3 ) Overweight (35% body fat) DIO (47% body fat) Dr. Nomeli Nunez Nunez, et al., Nutrition and Cancer, 2007
31 Genetic Reduction of Systemic IGF-1 ~75% of IGF-1 in serum is produced by liver Serum IGF-1 IGF-1, ng/ml WT LID Ecuadorians with Laron Syndrome have very low IGF-1 and inflammatory cytokines, increased longevity, and virtually no cancer or diabetes. NY Times 2/16/11.
32 Wnt-1 Mammary Tumor Growth in Wild-Type Control and Liver IGF-1 Deficient (LID) Mice Tumor Vol (mm3) Serum IGF-1 Levels Serum Insulin Levels Wild-Type LID Days after tumor cell injection * Dr. Nikki Ford Ford, et al. Endocrine-Related Cancer, 2013
33 Dietary Energy Balance Modulation of Akt/mTOR Signaling (normal and tumor tissue) (Insulin, IGF-1) RTK PI3K Obesity Calorie Restriction Skin Liver Prostate Colon Pancreas Mammary Akt GSK-3 Cyclin D mtor 4E-BP1 p70s6k Hursting, et al., Cancer Res, 2007 Moore, et al., Cancer Prev Res, 2008; S6 ribosomal Olivo-Marston, et al., Mol Carcinogenesis 2009 Lashinger, et al, Cancer Prev Res, 2011 Proliferation Translation Blando, et al., Cancer Prev Res, 2011 Nogueira, et al, Endocr Rel Cancer, 2012 deangel, et al., Mol Carcinogenesis, 2013
34 The mtor Inhibitor RAD001 (Afinitor ) Inhibits Wnt-1 Mammary Tumor Growth in Lean, Control and Obese Mice DeAngel, et al. Mol Carcinogenesis, 2013
35 The Obesity-Cancer Link Energy Balance and Breast Cancer Prevention: Transdisciplinary Research Approaches Increased Increased Hormone/ InsR/IGF-1R Growth Factor Signaling Signaling
36 Integrated Phase II Trial and Animal Studies of Lovaza (omega-3-acid ethyl esters) High-Risk Women Lovaza (4g/d) C. Fabian, MD Placebo 1 yr Serum/Benign Breast Tissue Biomarkers 1. Response: Ki-67, cytomorphology 2. Mechanism: qrtpcr: ER-genes; mir s; Proteomics: mtor, MAPK signaling; Cytokines Mouse Models Lovaza (208 mg/kg diet) Change in Biomarkers Cancer Endpoint S. Hursting, PhD, MPH Placebo 3 mos Breast Cancer Research Foundation Grant; Susan Komen Foundation Grant
37 May, 2014 * 2030 * 2030
38 Obesity Causes Inflammation in Pancreas and Adipose Tissue Crown-like Structures (CLS) (Macrophage/Adipocyte/Epithelial Tumor Cell Interactions)
39 Dietary Energy Balance Affects Pancreatic Tumor-Free Survival in Kras Ink4a +/- Mice % Survival Kras G12D /Ink4a +/- DIO Control c CR Weeks on Diet DIO increases, CR decreases: - Fatty pancreas a b - Pancreatic CLS, inflammation CR - Serum insulin, IGF-1 levels CON - Leptin:Adpn DIO - Serum cytokine levels - Akt/mTOR signaling Lashinger, et al., Cancer Prev Res 2013
40 Take-Home Messages Many cancers (~2 out of 3) are preventable Recommendations: 1. consume diet rich in vegetables, fruits, whole grains, and lean protein 2. avoid weight gain (and limit sugary food/drink) 3. be physically active 4. avoid tobacco; alcohol in moderation 5. follow your doctor s recommendations on screening (eg, colonoscopy; mammograpy; prostate exams; pap smears; skin checks) Ongoing transdisciplinary research at NRI is focused on molecular and metabolic targets and intervention strategies to prevent cancer
41 Karrie Wheatley Lauri Lashinger Susan Perkins Alison Harvey Jason Goldberg Leticia Nogueira Rebecca DeAngel Sarah Smith Audrey Rasmussin Lauren Malone
42 Acknowledgements University of Texas at Austin John DiGiovanni, Michele Forman, Nomeli Nunez, Rong Cui University of Texas-M.D. Anderson Cancer Center Sue Fischer, Donna Kusewitt, JJ Shen, Powel Brown Mt. Sinai Medical Center Derek LeRoith, Shoshana Yakar National Cancer Institute Curt Harris, Chuck Vinson, Lyuba Varticovski Kansas University Medical Center UNC-Chapel Hill Carol Fabian, Brian Petroff, Bruce Kimler Sergey and Natalia Krupenko, Chuck Perou, David Darr, Liza Makowski Weill-Cornell Cancer Center Andrew Dannenberg Funding: National Cancer Institute, National Institute of Environmental Health Sciences, American Institute for Cancer Research, Breast Cancer Research Foundation, Susan G. Komen Foundation
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