Breakfast Session II: 7 8:15 am Diet, Inflammation, and Cancer Prevention
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1 Breakfast Session II: 7 8:15 am Diet, Inflammation, and Cancer Prevention James C. Fleet, PhD Distinguished Professor Department of Nutrition Science Purdue University Gregory B. Lesinski, PhD MPH Associate Professor Department of Hematology and Medical Oncology Emory University School of Medicine
2 What is Cancer Prevention? Cancer Treatment Cancer Prevention Survival with Cancer Diagnosis Survival without Cancer Time (y) Umar et al. (2012) Nat. Rev. Cancer 12:835 Fleet 2016
3 Hallmarks of Cancer: A Genomic Disease Sustained Proliferation Resist Apoptosis Avoid Growth Suppression Achieve Immortality Hanahan and Weinberg, 2006
4 The Molecular Signature of Colon Cancer Chemoprevention Distal Colon and Rectum Proximal Colon Fleet Fearon 2004 and Vogelstein, 1990, Cell 61:759 Fleet 2016
5 If genetic damage is the match that lights the fire (of cancer), inflammation may provide the fuel that feeds the flames. Dr. Fran Balkwill Barts Cancer Institute Queen Mary University of London
6 New Hallmarks of Cancer Involvement of the Immune System Avoid Immune Destruction Tumor Promoting Inflammation Hanahan and Weinberg, 2011
7 Innate Immunity Non-specific, Rapid 1 macrophage T cell B cell 2 ROS, RNS Romani (2004) Nature Rev Immunol 4:11-24 Adaptive Immunity Specific, slower
8 Colitis Stimulates Intestinal Immunity ulceration Gut microbiome damage Bleeding Mucosal Layer Epithelial Layer normal Immune cell infiltration and cytokines Chassaing, Aitken 2014, Curr Protoc Immunol 104: Uniit 15.24
9 Colitis-Enhances Tumorigenesis in Mice CAC; APC 580/+ 20 wk, 10% Incidence CAC;APC 580/+ 2% DSS, 5 or 7 10 wks 50% Incidence Size (mm) Size (mm) Xue et al. (2010) Mol. Cancer Res. 8:1095. Fleet 2016
10 Inflammation-Induced Cancer is Different Sporadic Cancer of the Distal Colon and Rectum Colitis Associated Colon Cancer Terzic Fleet 2004 et al. (2009) Gastroenterology 138:2101 Fleet 2016
11 How Does Inflammation Induce Carcinogenesis? microbes Possible Mechanisms: ROS or RNS-induced DNA damage Release of bacterial genotoxins Cytokine-induced Disruption of barrier Proliferation Suppression of apoptosis Terzic et al. (2010) Gastroenterology 138:2101
12 Severe Vitamin D Deficiency Enhances DSS-Induced Colitis Colitis examined 10 d after a 6 d course of DSS Many other dietary agents suppress colitis Lagishetty et al. (2010) Endocrinology 151:2423 Fleet 2016
13 How Does Nutrition Block Inflammation or its Effects? microbes Change the Gut Microbiome/Alter the Insult Monday Morning Split Session A: Dietary Modulation of the Microbiome and Cancer Risk Terzic et al. (2010) Gastroenterology 138:2101
14 Dietary Interventions that Reduce Colitis- Associated Cancer Change the Gut Microbiome Curcumin Eicosapentanoic Acid (EPA) 0.5% Cur IL10 KO AOM EPA AOM+DSS McFadden et al Inflamm. Bowel Dis. 21:2483 Piazzi et al Intl. J Cancer 135:2004
15 How Does Nutrition Block Inflammation or its Effects? microbes Direct effect on epithelial cells: Anti-proliferative Pro-apoptotic Regulate tight junctions Protect from ROS Protect from cytokines Terzic et al. (2010) Gastroenterology 138:2101
16 1,25(OH) 2 D Suppresses Pro- Inflammatory Cytokine Signaling in PEC RWPE1 Normal prostate cells 100 nm, 1,25(OH) 2 D microarray Kovalenko et al BMC Genomics 11:26 Fleet 2016
17 1,25(OH) 2 D Induces Antioxidant and DNA Protective Mechanisms in PEC = ChIP-seq peak GSA c2. 6h NRF2 TFs MAFB 4.68 MAFF 1.94 MAFK 1.27 Fleet 2016
18 Dietary Lipids Can Be Anti-Inflammatory Linolenic acid Membrane composition 5LOX EPA DHA 15LOX COX1 COX2 5LOX COX2 GPCR PPAR GPCR PKA/cAMP Resolvins Protectins Inflammation Hou et al. (2016) Annu Rev Nutr 36:543 Greene et al. (2011) Prostagl Other Lipid Mediat 96:27 Barbalho et al. (2016) Ann Gastroenterol 29:37
19 How Does Nutrition Block Inflammation or its Effects? microbes Direct effect on Immune cells: Multiple cell targets Terzic et al. (2010) Gastroenterology 138:2101
20 n=8/group 8 wk M + F C57BL/6J Increased DSS Effect with Loss of Vitamin D Deficiency Vitamin D Signaling Intestine- Recovered VDR KO Colon Epithelium- Specific VDR KO Body Weight 1.35% DSS 5 days * % Body Weight Change 6 CAC CAC;VDR KO ns Day Post DSS Colon Inflamm. * * Fleet 2015
21 Nutrients Regulate Immune Cells Vitamin A Zn Vitamin C Vitamin A Vitamin E Zn Zn Vitamin A Vitamin E Se Vitamin A Vitamin C Fleet 2016 Hewison (2011) Vitamin Horm. 86:23
22 1,25(OH) 2 D Influences MΦ Biology 2 1 Proinflammatory 3 Tolerogenic Fleet 2016
23 1,25(OH) 2 D Influences MΦ Biology CD68 staining 2.5X TNFα IL1β IL6 Dougherty et al. (2014) Clin Cancer Res 20:5848
24 Schreiber et al. (2011) Science 331:1565 A Healthy Immune System Can Clear Transformed Cells Inflammation
25 Immunodeficient A Healthy Immune System is Needed to Fight Cancer Immunodeficient Immunocompetent Immunocompetent Shankaran et al. (2001) Nature 410:1107 Schreiber et al. (2011) Science 331:1565
26 The Tumor Microenvironment is Complex Immune Inflammatory Cells
27
28 Fleet Lab Current: Krittikan Chanpaisaeng, Ryan Calvert Past Cancer Project Members: Kate Barzan, Grant Burcham, Marsha DeSmet, Robert Johnson, Pavlo Kovalenko, Yan Li, Yingben Xue, Richard Zhang Fleet 2016 Acknowledgements Ohio State University Steven K. Clinton Purdue University Timothy Ratliff Brian Dilkes Paul Snyder Kiki Fairfax U of Colorado U of Eastern Scott Cramer Finland Tufts University Carsten Carlberg Jimmy Crott Univ. of Tokyo NIH Shigeaki Kato Terry Van Dyke NIH/NCI/NIDDK AICR Showalter Trust Purdue University Center for Cancer Research
29 How Does Inflammation Promote Cancer?
30 Tumors Can Escape Immune Surveillance Schreiber et al. (2011) Science 331:1565
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