Diet Induced Changes in Inflammation as Determinants of Colon Cancer

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Program Announcement Diet Induced Changes in
Inflammation as Determinants of Colon Cancer
Young S. Kim Nutritional Science Research
Group Division of Cancer Prevention
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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 Crohns disease have been shown to
increase the risk of colon cancer. ? Use of
anti-inflammatory agents such as aspirin have
shown to reduce the risk of colon cancer.
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The Inflammatory Process
Inflammatory signals Proinflammatory
cytokines Protein kinase C activation Viruses
Anti-inflammatory cytokines

(TGF-ß)
Inflammatory proteins Receptors Chemokines
Adhesion molecules Enzymes Cytokines
TNF-a Interleukin-1b
I-?B
NF-kB
Amplifying loop
mRNA
p50
p65
Nucleus
Inflammatory gene
Modified from Barnes, PJ et al. NEJM 3361066-71,
1997
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Genetics, Inflammation Colon Cancer Prevention
Anti-inflammatory Mediators
(IL-10, TGFß, etc.)
Genetic Polymorphisms and Dietary Factors??
Pro-inflammatory Mediators
(IL-6, TNFa, COX2)
Cancer Risk
High
Low
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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 Ge
nistein Luteolin Quercetin Resveratrol


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Specific Targets for Dietary Components
Inflammatory signals Proinflammatory
cytokines Protein kinase C activation Viruses Oxid
ants
Anti-inflammatory cytokines

(TGF-ß)
Curcumin EGCG, Luteolin N-3 fatty acids Quercetin
Inflammatory proteins Receptors Chemokines
Adhesion molecules Enzymes Cytokines
TNF-a Interleukin-1b
I-?B
Butyrate
Curcumin CLA
NF-kB
Amplifying loop
Resveratrol
mRNA
p50
p65
Nucleus
Inflammatory gene
Modified from Barnes, PJ et al. NEJM 3361066-71,
1997
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Green Tea Suppresses Cytokine Synthesis
TNF-a
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
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TNF-a Polymorphism Influences the Response to
Fish Oil in Humans
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Control
10
Fish Oil
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TNF-a Production (µg/l)
6

4
2
0
G/A
G/G
TNF-a Polymorphism at -308
Grimble et al. Am J Clin Nutr 76454-9, 2002.
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Preclinical, Epidemiological and Clinical
Evidence Suggests Diet, Inflammation, and Colon
Cancer May Be Interrelated
??
Inflammation
Colon Cancer
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Purpose of this PA
Use R01 and R21 mechanisms to foster probing
research that will determine if diet induced
shifts in inflammatory processes account for the
anti-tumorigenic effects of bioactive food
components on colon cancer.
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Various Models May Be Used in this PA
? Humans ? Genetic polymorphisms in
inflammatory mediators ? Inflammatory Bowel
Disease (e.g. Crohns 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
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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 ß-Catenin ? Dysplasia or Adenomas of
Colon
? Colon cancer incidence
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Some Overarching Topics of Interest
? Are NF?B and IKK activities responsible for
the efficacy of resveratrol and curcumin in
retarding colon cancer cell growth? ? Can
genetic polymorphisms in TNF-a 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?
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FY04 NCI Extramural Portfolio Analysis


(M)
2,940
100.0
Total
347
1,023
Cancer Prevention
11.8

198
796
6.7
Nutrition

179
33
1.2
Inflammation
7
0.02
0.5
Combination

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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)