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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. Colon Cancer and Inflammation. ● Colon cancer is the 2 nd leading cause of cancer deaths in the United States.

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slide1

Program Announcement:

Diet Induced Changes in Inflammation as Determinants of Colon Cancer

Young S. Kim

Nutritional Science Research Group

Division of Cancer Prevention

slide2

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.

slide3

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
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

slide5

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

slide6

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

slide7

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

slide8

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.

slide9

Bioactive Food Components

Preclinical, Epidemiological and Clinical Evidence Suggests Diet, Inflammation, and Colon Cancer May Be Interrelated

??

Inflammation

Colon Cancer

slide10

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.

slide11

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
slide12

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

slide13

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
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

slide15

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)

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