Evidence for the Relationship Between Nutrition and Cancer

Transcription

1 Keynote Lecture Evidence for the Relationship Between Nutrition and Cancer Dr. Sharon Ross National Cancer Institute, Bethesda, MD, USA

2 Evidence for the Relationship Between Nutrition and Cancer Prevention Sharon Ross, PhD, MPH Nutritional Science Research Group Division of Cancer Prevention National Cancer Institute Bethesda, MD

3 The World Is Changing: Projected Deaths In 2010, cancer will become the world s leading cause of death

4 About 25,000 Bioactive Food Components Unprecedented opportunities exist to achieve genetic potential, increase productivity and reduce the risk of disease, including cancer Multiple Interactions

5 It has been estimated that about 1/3 of all cancer deaths may be attributable to dietary factors. Evidence Based Report Showcases Inconsistencies in the Effect of Diet on Cancer Prevention Diet 35% Other Factors 35% Tobacco 30% The Causes of Cancer Richard Doll & Richard Peto, 1981 WCRF/AICR Report - Released Nov. 1-2, 2007

6 WCRF/AICR Report 2007 Why Is the Evidence Not More Compelling??

7 Literature is Full of Inconsistencies: Breast Cancer: Soy Intake Asian Western Lee 92 (total soy protein) p < Premenopausal NS Postmenopausal Hirose 95 (bean curd, miso) Yuan 95 (tofu, soymilk) NS Premenopausal NS Postmenopausal NS p = Shanghai, Tianjin Wu 96 (tofu) p < 0.01 Premenopausal p < 0.05 Postmenopausal Key 99 (soy) Tofu Miso Zheng 99 (urinary isoflavonoids) Dai 01 (soy) NS All Breast Cancer S Just ER + /PR + Wu 02 (soy) Yamamoto 03 (isoflavonoid consumption) Premenopausal Postmenopausal Wu 04 (soy) Ingram 97 (urinary isoflavones) NS Diadzein p = Equol Witte 97 (soy) den Tonkelaar 01 (urinary phytoestrogens) NS Postmenopausal Horn-Ross 01 (phytoestrogen intake) Keinan-Boker 02 (food content) NS Isoflavones S Lignans Linseisen 04 (isoflavone intake) daidzein and genistein

8 Lots of Variability in Prospective Studies High vs. Low Tomato Intake or Lycopene & Prostate Cancer RR (95% CI) Mills, 1989 Hsing, 1990 Giovannucci, 1995 Nomura, 1997 Schuurman, 1998 Cerhan, 1998 Gann, 1999 Giovannucci, 2002 Huang, 2003 Huang, 2003 Wu, 2004 plasma-based dietary-based

9 Part of Confusion Arises from Trying to Use Population Information to Predict Individual Responses

10 Comparing People Is a Little Like Comparing Apples and Oranges! =

11 What Is Nutrigenomics About? Understanding variation in response with the help of the Omics and Molecular Targets Bioactive Food Component N u t r i g e n o m i c s Nutrigenetics Nutritional Epigenetics Nutritional Transcriptomics DNA RNA Protein Phenotype Proteomics Metabolomics Metabolite Bioactive food components can be introduced at points of initiation, promotion, & progression to potentially disrupt the pathway leading to an unhealthy or lethal phenotype

12 Future Is To Focus on the Process Needing Modification Credentialing of nutrients and molecular targets is likely the future? Credentialing is defined as omic changes that bring about a phenotypic change

13 XRCC1 (Arg399Gln) Polymorphisms May Influence the Response to Lycopene Lycopene Intake (µg/day) n=77 CaP pts; n=174 controls Arg/Gln + Gln/Gln low-risk High 0.82 ( ) Medium 0.97 ( ) Arg/Arg high-risk 0.21 ( ) 0.59 ( ) Low Goodman et al., (2006) Nutr. CA, 55(1): *P trend < 0.01

14 OR for Colon Cancer Genetic Information May Assist in Identifying Those Who Must Assure Adequate Intakes * Wong et al. Carcinogenesis, 24: , 2003 * FF Ff ff VDR Genotype Dietary Calcium < 388 mg/day >388 mg/day P for trend=0.004

15 Genetic Information May Help Identify Those Who Might Benefit from Limiting Intakes of Specific Foods France: 1,023 CRC cases and 1,121 controls Odds Ratio: Colon Cancer * ** Red Meat Intake < 5 Times/Wk 5 > Times/Wk * P = ** P < Multi-CYP SNPs: CYP1A2-163A>C 1548T>C CYP2E1-1293G>C -1053C>T CYP1B1 1294C>G CYP2C9 430C>T Population 4.4% Diet Kury et al. (2007) CEBP, 16: SNP Inter + Diet Does the increase risk relate to a change in a cancer related process???

16 Balance of Foods Important: High Amylose Maize Starch and Red Meat Ameliorates DNA Damage Toden et al. 2007Carcinogenesis. 28(11):

17 Diet and GWAS are beginning!! Ferguson et al. (2007) Cell Mol Life 64(23): Not all that enlightening probably because can t monitor intake of specific bioactive components in the diet

18 Sample Kit 23 and Me Genotyping -$399 /saliva kit -Results in 2-4 weeks -Illumina HumanHap BeadChip reads nearly 600,000 SNP s -Uploads information to online database -Has odds calculator to suggest common health concerns for person with specific genetic composition Compare your genes with friends, family and the world!! Exceeding complex area since about 30, 000 Genes, 8-10 Million SNPs Illumina HumanHap BeadChip

19 Genetic Testing Promises vs. Reality! Commercial Nutrition-Gene Test Sciona 19 genes determines whether your DNA contains gene variants that have been associated with 5 key health areas: bone health, heart health, antioxidant/detoxification, insulin sensitivity, and inflammation. Cost about $300. Genelex The panel examines 19 genes that play major roles in your body's detoxification capacity, antioxidant capacity, heart health, bone health, insulin sensitivity, and tissue repair. About $500.

20 The overall contribution of Copy Number Variance (CNV) to complex phenotypes Expression levels of 14,925 transcripts with SNPs and CNVs in individuals who are part of the International HapMap project was evaluated. SNPs and CNVs captured 83.6% and 17.7% of the total detected genetic variation in gene expression, respectively. The signals from the two types of variation had little overlap Stranger et al (2007) Science. 315(5813):848-53

21 Diet and Human Amylase Gene Copy Number Perry et al. (2007) Nature Genetics 39(10):

22 Personalized Medicine and Personalized Nutrition Recent advances: Herceptin is a Novel Pioneering Drug for Personalized Medicine Approach Based on Pharmacogenomics to block Her2-neu expression. Evidence Has Existed for Some Time: EGCG from Green Tea, Oleic Acid from Olive Oil, and n-3 fatty acids from Fish Oil and Apigenin from parsley, thyme, and peppermint since they also may also significantly influence HER2neu expression!

23 Herceptin and Dietary fish oil increased the latency time to mammary gland tumor development in the HER-2 transgenic mice 1.0 Herceptin 1.0 Disease-free Survival Control Disease-free Survival Fish Oil Corn Oil Months Finkle D et al Clin Cancer Res 10: , Months Yee LD et al J Nutr 135: 983-8, 2005

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25 Epigenetics Definition Genetics: the study of heritable changes in gene function that occur with a change in the DNA sequence Epigenetics: the study of heritable changes in gene function that occur without a change in DNA sequence. Changes in gene expression without changes to DNA sequence passed on through cell division Study of the regulation of gene activity that is not dependent on gene sequence

26 Epigenetic Regulation of Cancer Regulating Factors Dietary Hormonal Genetic Epigenetics Regulates: Cell Cycle Control DNA Damage Apoptosis Invasion X-Chromosome Inactivation Imprinting Aging DNA Methyltransferases Histone Methyltransferases Histone Acetylases/Deacetylases Global Hypomethylation Site Specific Hypermethylation Hypomethylation Histone Modifications Verma M, Srivastava S. Lancet Oncol. (2002) 3:

27 Epigenetic Changes in Twins Fraga et al (2005) PNAS 26;102(30):

28 Foods Can Also Influence Epigenetics

29 LTR Hypomethylated LTR Hypermethylated Maternal Supplements with zinc, methionine betaine, choline, folate, B 12 Or Genistein Yellow Mouse High risk cancer, diabetes, obesity & reduced lifespan Agouti Mouse Lower risk of cancer, diabetes, obesity and prolonged life Cooney et al. J Nutr 132:2393S (2002); Dolinoy et al. Envir. Health Perspect 114: 567 (2006)

30 Histone Modifications Influence Gene Expression Gene switched on : open chromatin, unmethylated cytosines, acetylated histones Gene switched off : closed chromatin, methylated cytosines, deacetylated histones

31 HDAC Inhibition by Sulforaphane-rich Broccoli Sprouts in Human Volunteers Dashwood RH, Ho E. Semin Cancer Biol. 2007

32 Dietary Intervention Can Cause Shifts in Transcriptomic Expression

33 Low-Fat Feeding and Gene Expression in Human Prostate Epithelium Lin et al. Cancer Epidemiol Biomarkers Prev. 2007;16:2150-4

34 The Foundation of Nutrition and Cancer Prevention Are Controlled Dietary Interventions Studies in Humans Lappe et al. Am J Clin Nutr 2007;85:

35 Dietary Interventions May Not Always be Protective Today Concern About Excess Calcium Iron Folic Acid Selenium Vitamin A Vitamin D Others??? Why does this differential response occur? Normal vs neoplastic cells?? The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. N Engl J Med. 330: , Albanes et al. AJCN 62:1427S-1430S, 1995.

36 Timing Is Also Very Important Linxian Nutrition Intervention Trial Esophageal cancer mortality by factor D (N=1515) Factor D= Selenium, β-carotene, vitamin E Log-rank P=0.024 RR=0.83 <55 years Placebo Factor D Log-rank P=0.045 RR= years Factor D Placebo Esophageal Cancer Death Time (Year) Esophageal Cancer Death Time (Year) Taylor, P. et al., Gastroenterology 2005 (abstract). Qiao YL, et al. JNCI 101:507-18, 2009.

37 Stage of cancer appears to influence response to folate (Apc+/- Msh2-/- mouse) Start Diet 3 weeks 3 weeks 6 weeks 6 weeks Dietary folate (mg 0 (n = 7) 8 (n = 7) 0 (n = 10) 8 (n = 7) folate/kg diet) Duration of folate intervention (weeks) Serum folate (ng/ml) 15.0 ± ± 7.7** 19.8 ± ± 27.0** Average number of total small intestinal adenomas per mouse ± ± 5.2** 70.0 ± ± 59.6** Song et al. (2000) Cancer Res 2000;60: 3191 Replicated in the Apc min mouse: Cancer Res 2000;60: 5434

38 Age-adjusted U.S.A. CRC incidence, , SEER database fortification begins Mason J, et al. Cancer Epidemiol Biomarkers Prevent 16: , 2007.

39 Fundamental Question Remains About True Site of Action of Functional Foods and Their Active Constituents Bioactive Food Component(s)

40 Multiple Food Constituents Can Influence One Nuclear Transition Factor Garlic, fish, broccoli, tomatoes Active Intermediate (radical??) Caloric Restriction keap-1 nrf2 Agent HS SH S S keap-1 Cytoplasm nrf2 small maf ARE antioxidant responsive element nrf2 Nucleus Increased GST, QR

41 Lycopene Influences Multiple Pathways, which are linked in crosstalk in prostate cancer development, resulting in anti-inflammation, growth reduction & apoptosis induction LPS bacterial infection NFκB TLR4 IL-6 (and others) Lyc IL-6 inflammation Jak STAT3 STAT3 Lyc IL6R/ gp 130 Jak AR STAT3 IGF-I or EGF, PDGF.. MAPK AP1 R-PTK Lyc PI3K T DHT AR Lyc Lyc Lyc AKT DHT DHT AR AR β-catenin AR Wnt DSH GSK3β Frz Axin β-catenin APC Lyc TCF β-catenin Bad caspase 9 FHKR FOXO E Cdh Cell adhesion neighboring cell Lyc gap junction inhibition of inflammation inhibition of cell growth by G1/S cell cycle delay Induction of apoptosis Wentz 2008 Personal Communication

42 Biomarkers Are Needed

43 One Size Does Not Fit All!

44 WCRF/AICR Recommendations 1. Be as lean as possible without being underweight 2. Be physically active. 3. Avoid Sugary drinks. 4. Eat more of a variety of vegetables, fruits, whole grains, and legumes. 5. Limit consumption of red meats 6. If consume alcohol do so in moderation 7. Limit consumption of salty foods 8. Supplement use: meet nutritional needs through diet alone

45 Thanks for your attention! Questions?

46 Symposium Nutrition and Cancer Minder kanker en betere behandelresultaten door gezonde voeding?