# Presentation: 136114

## Program Announcement: 

**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.**
**●** **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 as** 	**aspirin have shown to reduce the risk ****	****of colon cancer.**

## The Inflammatory Process

- NF-B

- Nucleus

- Inflammatory gene

- Amplifying loop

- mRNA

**p50**

**p65**

- TNF-
- Interleukin-1

- I-ĸB

**The Inflammatory Process**

- Anti-inflammatory cytokines                                                                                        (TGF-β)

- Inflammatory signals
- Proinflammatory cytokines
- Protein kinase C activation
- Viruses

- Inflammatory proteins
- Receptors
- Chemokines
- Adhesion molecules
- Enzymes
- Cytokines

- Modified from Barnes, PJ et al. NEJM 336:1066-71, 1997

## Genetics, Inflammation & Colon Cancer Prevention

**Genetics, Inflammation & Colon Cancer Prevention**

**Genetic Polymorphisms ****and **
**Dietary Factors??**** **

**(IL-10, TGF****β****, etc.)**

**Anti-inflammatory**
**Mediators**** **

**(IL-6, TNF****α****, COX2)**

**Pro-inflammatory**
**Mediators**

**Cancer Risk**

**High**

**Low**

## Dietary Components Linked to Reduced Colon Cancer Risk

_**Fatty Acids**_
**N-6: Conjugated linoleic acid **
**N-3: Docosahexaenoic acid**
**         ****Eicosapentaenoic acid **
**Short chain: Butyrate**

_**Polyphenols**_
**Curcumin**
**Epigallocatechin-3-gallate**
**Genistein**
**Luteolin**
**Quercetin**
**Resveratrol**

_**Minerals**_
**Calcium Selenium**

_**Vitamins**_
**Vitamin A **
**Vitamin D  Folate**

## Specific Targets for Dietary Components

- NF-B

- Nucleus

- Inflammatory gene

- Amplifying loop

- mRNA

**p50**

**p65**

- TNF-
- Interleukin-1

- I-ĸB

**Specific Targets for Dietary Components**

- Anti-inflammatory cytokines                                                                                        (TGF-β)

- Inflammatory signals
- Proinflammatory cytokines
- Protein kinase C activation
- Viruses
- Oxidants

- Inflammatory proteins
- Receptors
- Chemokines
- Adhesion molecules
- Enzymes
- Cytokines

**Curcumin**
**EGCG, Luteolin**
**N-3 fatty acids**
**Quercetin**

**Butyrate**

**Resveratrol**

**Curcumin CLA**

- Modified from Barnes, PJ et al. NEJM 336:1066-71, 1997

## Green Tea Suppresses Cytokine Synthesis

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**80**

**90**

**100**

**% of control**

**0.1% Green tea extract**

- -

- -

**+**

**+**

**TNF-****α**

**IL-6**

- Sueoka N et al, Ann N Y Acad Sci 928: 274-80, 2001

******

*****

## TNF-α Polymorphism Influences the Response to Fish Oil in Humans

**TNF-****α**** Production (μg/l)**

**G/G**

**G/A**

**TNF-****α**** Polymorphism at -308**** **

**0**

**Control**

**Fish Oil**

**2**

**4**

**6**

**8**

**10**

**12**

******

- Grimble et al. Am J Clin Nutr 76:454-9, 2002.

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

**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 induced**** ****shifts 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**

**●**** ****Aberrant Crypt Foci**** (ACF): Number, ****	****size, the content of ****β****-Catenin**
**● ****Dysplasia ****or**** Adenomas**** of Colon**
**● ****Colon cancer incidence**

- Diet induced changes in the inflammatory process must be coupled with:

## Some Overarching Topics of Interest

**●****  ****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?**

**Some Overarching Topics of Interest**

## FY04 NCI Extramural Portfolio Analysis

**  ****#**

**$ (M)**

**%**

**Cancer Prevention**

**   **

**  ****11.8**

**Inflammation**

**   **

**    ****6.7**

**Nutrition**

**    ****1.2**

**Combination**

** **

**    ****0.5**

**  ****0.02**

**Total**

**100.0**

**2,940**

**347**

**33**

**198**

**7**

**1,023**

**796**

**179**

## 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)**