Program Announcement: Diet Induced Changes in Inflammation as Determinants of Colon Cancer Young S. Kim Nutritional Science Research Group Division of Cancer Prevention
Colon Cancer and Inflammation ● Colon cancer is the 2nd leading cause of cancer deaths in the United States. ●Chronic inflammatory bowel diseases such as ulcerative colitis or Crohn’s disease have been shown to increase the risk of colon cancer. ● Use of anti-inflammatory agents such asaspirin have shown to reduce the risk of colon cancer.
The Inflammatory Process Inflammatory signals Proinflammatory cytokines Protein kinase C activation Viruses Anti-inflammatory cytokines (TGF-β) Inflammatory proteins Receptors Chemokines Adhesion molecules Enzymes Cytokines TNF-a Interleukin-1b I-ĸB NF-kB Amplifying loop mRNA p50 p65 Nucleus Inflammatory gene Modified from Barnes, PJ et al. NEJM 336:1066-71, 1997
Genetics, Inflammation & Colon Cancer Prevention Anti-inflammatory Mediators (IL-10, TGFβ, etc.) Genetic Polymorphisms and Dietary Factors?? Pro-inflammatory Mediators (IL-6, TNFα, COX2) Cancer Risk Low High
Dietary Components Linked to Reduced Colon Cancer Risk Fatty Acids N-6: Conjugated linoleic acid N-3: Docosahexaenoic acid Eicosapentaenoic acid Short chain: Butyrate Minerals Calcium Selenium Vitamins Vitamin A Vitamin D Folate Polyphenols Curcumin Epigallocatechin-3-gallate Genistein Luteolin Quercetin Resveratrol
Specific Targets for Dietary Components Inflammatory signals Proinflammatory cytokines Protein kinase C activation Viruses Oxidants Anti-inflammatory cytokines (TGF-β) Curcumin EGCG, Luteolin N-3 fatty acids Quercetin Inflammatory proteins Receptors Chemokines Adhesion molecules Enzymes Cytokines TNF-a Interleukin-1b I-ĸB Butyrate Curcumin CLA NF-kB Amplifying loop Resveratrol mRNA p50 p65 Nucleus Inflammatory gene Modified from Barnes, PJ et al. NEJM 336:1066-71, 1997
Green Tea Suppresses Cytokine Synthesis TNF-α IL-6 100 90 * 80 70 ** % of control 60 50 40 30 20 10 0 - - + + 0.1% Green tea extract Sueoka N et al, Ann N Y Acad Sci 928: 274-80, 2001
TNF-α Polymorphism Influences the Response to Fish Oil in Humans 12 Control 10 Fish Oil 8 TNF-α Production (µg/l) 6 ** 4 2 0 G/A G/G TNF-α Polymorphism at -308 Grimble et al. Am J Clin Nutr 76:454-9, 2002.
Bioactive Food Components Preclinical, Epidemiological and Clinical Evidence Suggests Diet, Inflammation, and Colon Cancer May Be Interrelated ?? Inflammation Colon Cancer
Purpose of this PA Use R01 and R21 mechanisms to foster probing research that will determine if diet inducedshifts in inflammatory processes account for the anti-tumorigenic effects of bioactive food components on colon cancer.
Various Models May Be Used in this PA • ● Humans • ♦ Genetic polymorphisms in inflammatory mediators • ♦ Inflammatory Bowel Disease (e.g. Crohn’s Disease, Ulcerative colitis) • ● Animals • ♦ Colitis induced inflammation in colon • ♦ Transgenics (i.e. simultaneously expressing COX-2 and PGE2) • ♦ Double knockouts (i.e. APC x Ptgs2) • ♦ Xenografts
Required End Point Measurements for this PA Diet induced changes in the inflammatory process must be coupled with: ●Aberrant Crypt Foci (ACF): Number, size, the content of β-Catenin ● Dysplasia or Adenomas of Colon ● Colon cancer incidence
Some Overarching Topics of Interest ● Are NFκB and IKK activities responsible for the efficacy of resveratrol and curcumin in retarding colon cancer cell growth? ● Can genetic polymorphisms in TNF-α or IL-6 explain the differential responsiveness to n-3 fatty acids in fish oil with regard to colon cancer inhibition? ● Can the production of PGE2 and NO be influenced by dietary conjugated linoleic acid and ultimately modify colon cancer risk?
FY04 NCI Extramural Portfolio Analysis % # $ (M) 2,940 100.0 Total 1,023 347 Cancer Prevention 11.8 198 796 6.7 Nutrition 179 33 1.2 Inflammation 7 0.02 0.5 Combination
Concept Builds On ● Significance of colon cancer incidence and mortality in the USA ● Recognized effects of dietary components on colon cancer ● Role of inflammation as a factor for colon cancer ● Recommendations by: - NCI Colorectal Cancer Progress Review Groups (2000) -Nutritional Genomics and Proteomics in Cancer Prevention Workshop (DCP/NIH 2002) - “Cancer Prevention, Early Detection, and Prediction” (NCI Bypass 2006)