# Presentation: 575199

## Obesity, Energy Balance and Cancer PreventionStephen D. Hursting, PhD, MPHDivision of Cancer Prevention andNutrition and Molecular Carcinogenesis Section Laboratory of Biosystems and CancerNational Cancer Institute

## Cancer Chemoprevention

**Aim:  Inhibit the development of cancer through pharmacological intervention before the appearance of a clinically detectable tumor.**

## The US Obesity    Epidemic(JAMA 10/9/02)

- 64.5% of US Adults Overweight – body mass index (BMI) >25.0 kg/m2
- 30.5% US Adults Obese – BMI > 30.0 kg/m2
- ~5% US Adults Extremely Obese – BMI > 40.0 kg/m2

**© ****Marty Bucella**

**Notes:**
5 feet 5 inches and 150 /180 lbs
5 feet 9 inches and 169/203 lbs
6 feet and 184/221 lbs

## Today’s Presentation

**Today’s Presentation**

**A nation out of energy balance:  the scope of the obesity problem in the US**
**Energy balance and cancer studies in transgenic mouse models:  IGF-1 as a molecular target**
**Effect of energy balance modulation on gene expression**

## *Obesity defined as  BMI > 30

- *Obesity defined as  BMI _>_ 30

## *Obesity defined as  BMI > 30

- *Obesity defined as  BMI _>_ 30

## *Obesity defined as  BMI > 30

- *Obesity defined as  BMI _>_ 30

## *Obesity defined as  BMI > 30

- *Obesity defined as  BMI _>_ 30

## *Obesity defined as  BMI > 30

- *Obesity defined as  BMI _>_ 30

## Prevalence of Obesity* Among U.S. Adults BRFSS, 2000

**Prevalence of Obesity* Among U.S. Adults BRFSS, 2000**

**<10%**
**10% to 14%**
**15% to 19%**
**≥****20%**

- *Obesity defined as  BMI _>_ 30

## Cancers Associated with Obesity

** ****Breast (postmenopausal)**
** ****Endometrium****	****	**
** ****Cervical**
** ****Ovarian**
** ****Colorectal**
** ****Kidney**
** ****Liver/ Gall Bladder **
** ****Pancreatic**
** ****Esophageal**
** ****Hematopoietic**

** ****Prostate**
** ****Colorectal**
** ****Kidney**
** ****Liver/Gall Bladder**
** ****Pancreatic**
** ****Esophageal**
** ****Hematopoietic**

_*In Men*_

_*In Women*_

- ACS, 2002

## Nutrition and Molecular Carcinogenesis Section, 

- Nutrition and Molecular Carcinogenesis Section,
- NCI Laboratory of Biosystems and Cancer

## The Multi-Disciplinary Approach to 

**Cancer Prevention Research**

**Animal Model**
**Studies**

**Clinical/Epidemiologic**
**Studies**

**Basic Molecular/**
**Cellular Studies**

**Identify**
**Risk Factors &**
**Mechanisms**

**Effective Human Interventions**

**Behavioral Studies**

## Central Question

**Can we offset increased cancer risk due to a genetic lesion ****(e.g., loss of p53 tumor suppressor function)**** by preventive approaches?**
** ****(Focus: diet, energy balance)**

## The Accumulation of Genetic Alterations 

**in Human Colon Carcinogenesis**

** **

- BMJ 10/1/00

## Energy Balance and Cancer Prevention

- Energy
- Balance

- Amount
- Type
- Pattern

- Physical Activity
- Growth
- Storage
- Routine Metabolism
- Thermoregulation

- Energy in

- Energy out

## p53-/- Mice 

**spontaneous**
**rapid**
**relevant to human cancer**
***responsive to interventions?***

**Attractive tumorigenesis model since ****tumor development is:**

## The Effect of 40% Calorie Restriction on

** ****Body Size in p53-/- Mice**

** **

## The Effect of 40% Calorie Restriction on 

**Survival in p53-/- and p53+/+ Mice**

**p<0.001**

**p<0.001**

- Hursting, et al.  *Cancer Res* 1997

- IGF-1 (ng/ml) :	    648	             373	       660		    365

## Calorie Restriction Extends Lifespan and 

- 0

- 5

- 10

- 15

- Hereford Cow

- Labrador Retriever

- F344 Rat

- Sprague-Dawley Rat

- C3B10RF1 Mouse

- p53+/+ Mouse

- p53-/- Mouse

**Age (Years)**

**44 %**

**37 %**

**56 %**

**32 %**

**39 %**

**16 %**

**35 %**

**Calorie Restriction Extends Lifespan and **
**Delays Neoplasia in Multiple Species**

- Hursting, et al., *Ann Rev Med*, 2002

## The Effect of  Dietary Restriction on Spontaneous Tumorigenesis in Aged Male p53+/- Mice

**Study start: all mice 9-10  months of age **

- Berrigan*, *et al.* Carcinogenesis*, 2002

**p=0.04**

**p =0.002**

## Treatment Effects on Serum IGF-1 and 

**Leptin Levels in p53+/- Mice**

**Control****	****514 **_**+**_** 14****	****15.9 **_**+**_** 1.9****	**
**Calorie Restriction****	****387* **_**+**_** 30****	**** 4.9* **_**+**_** 1.1**
**1-Day/Week Fast****	****463* **_**+**_** 17****	****19.6 **_**+**_** 1.5**
**	**

**Treatment****	****	**** IGF-1****	****Leptin**
**	****	****(ng/ml)****	****(ng/ml)**

**Mean **_**+**_** SE**

*** p (versus control) < 0.05**

- Berrigan*, *et al.* Carcinogenesis*, 2002

## Summary:  Models Responsive to 

**Summary:  Models Responsive to **
**Anti-Obesity Interventions**

**p53-/-, p53+/-, p53+/+ ****(spontaneous HN’s, sarcomas)**
**p53+/-: *****p*****-cresidine**** (6-month bladder model)**
**BK5.IGF-1 TG:*****p*****-cresidine**** (6-month bladder model)**
**p53+/- x MMTV-*****Wnt-1***** TG**** (spont. mammary tumors)**
**C3(1) -Large T Antigen TG**** (spont. mammary tumors)**
**p53+/-:  AOM (chemically-induced intestinal tumors)**
**APC****Min**** mice ****(spontaneous intestinal tumors)**
**	**

## Insulin-like Growth Factor (IGF)-1 and Cancer

**Insulin-like Growth Factor (IGF)-1 and Cancer**

**IGF-1 regulates mitogenic and apoptotic rates of epithelial cells **
**High serum levels of IGF-1 are significantly associated with risk of several cancers:  prostate ****(Chan, et al., *****Science***** 1998);**** premenopausal breast ****(Hankinson, et al., *****Lancet*****, 1998);**** lung ****(Wu, et al., *****JNCI*****, 1999);**** ****leukemia ****(Petridou, et al. *****Int J Cancer*****, 1999);**** bladder (****acromegaly; Higuchi, et al., *****Endocr J*****, 2000)**** **
**Calorie restriction inhibits cancer in multiple models; lowers plasma IGF-1; IGF-1 replacement reverses anti-cancer effects ****(Hursting et al., *****Cancer Res***** 1993; Dunn, et al., *****Cancer Res*****, 1997; Hursting et al., *****Ann Rev Med*****, 2003)****	**

## New Model Development in p53-Deficient Mice

**Approach:****	****Low-dose carcinogen induction ****	****	****in p53+/- mice**

***p*****-cresidine****, 4-aminobiphenyl (bladder)**
**azoxymethane (colon)****	****	**
**PhIP (colon, prostate)**
**MNU (mammary; lymphoma)****	**
**	****	****	****	****	**

## p-Cresidine

**2-methoxy-5-methylbenzeneamine**
**intermediate in azo dyes **
**dye industry:  high bladder cancer rate**

**NH****2**

**OCH****3**

**H****3****C**

## D.

- A.

- B.

- C.

- D.

**The Effect of Diet Restriction (+/- IGF-1) in **
***p*****-Cresidine-Treated p53-Deficient Mice**

## NCI Nutrition and Molecular Carcinogenesis Section

**Breaking Open the Black Box**

- Ad Lib v. CR v. CR + IGF-1

- Microarrays

## Effects of CR + IGF-1 on Gene Expression

- 0

- 20

- 30

- 40

***% Calorie Restriction***

***IGF-I ***
***(************g/day)***

- 0

- 20

- 40

- 80

- 5 mice per group, all females, 5 wks old at surgery

- X

- X

## Number of Genes Changedwith Increasing CR

| 
Percent Calorie Restriction | Mean of number of genes changed >2-fold and statistically significantly different |
| --- | --- |
| 20%  | 955 |
| 30% | 1092 |
| 40% | 1222 |

**Number of Genes Changed****with Increasing CR**

## Gene Expression Changes: Increasing CR

**Gene Expression Changes:**** Increasing CR**

- Increased by CR:	Sultn	N-sulfotransferase
- 			Sth2	Sulfotransferase, hydroxysteriod preferring
- 			Mgst3	Microsomal GST 3
- 			Gstt2	GST theta
- 			Gsta2	GST alpha
- 			Amd1	S-adenosylmethionine decarboxylase
- 			Mt1/2	Metallothionein 1 and 2
- 			Gadd45 Growth arrest with DNA damage
- 			Igfbp1	IGF-I binding protein 1
- Decreased by CR:	Hsd3b5	   Hydroxysteroid dehydrogenase 3b5
- 			Hsd17b2  17b Hydroxysteroid dehydrogenase
- 			EGFR	   Epidermal growth factor
- 			COMT	   Catechol O-Methyltrasferase
- 			CycD1	   Cyclin D1

## IGF-1-Dependent Gene Expression Changes(30% CR versus 30% CR + IGF-I)

**IGF-1-Dependent Gene Expression Changes****(30% CR versus 30% CR + IGF-I)**

-   58 genes differentially expressed
-   27 restored to ~AL control level
-   Examples of IGF-I-Dependent Changes
- 	- promote cell survival (Gadd45a; CycD1)
- 	- promote gene transcription
- 		(Onecut1, Foxa2)
- 	-decreased cell adhesion (dsc2)
- 	-IGF pathway (IGF BP1)

**Notes:**
The expression of 84 genes are taken from 42, 44, 52, 54 vs 2 comparisons.  One gene was Affy control which was removed.  No filtering of “A” and “NC” is applied because there are many missing values.  However, in general the average ratio of (52,54) vs. (42, 44) agreed with average ratio calculated by (52 vs 42, 54 vs. 44 etc.).

## Energy Balance and Cancer Prevention

- Energy
- Balance

- Amount
- Type
- Pattern

- Physical Activity
- Growth
- Storage
- Routine Metabolism
- Thermoregulation

- Energy in

- Energy out

## Slide 34

## Summary:  Interventions

**Summary:  Interventions**

**Calorie restriction (chronic) **_**+**_** IGF, leptin**
**1-day/week fast (cyclical restriction) **
**Treadmill/ running wheel exercise**
**Chemopreventive steroids (DHEA, fluasterone)**
**Chemopreventive nutrients/agents (soy, 4-HPR, Se, NSAIDs/COX inhibitors)**
**Combinations? (CR + exercise; CR + chemopreventives; chemopreventives + vaccines)**

## Acknowledgements

**Acknowledgements**

**	**

**National Cancer Institute**
**	**_**CP Fellows:**_**	****	**_**Investigators**_
**	****Jackie Lavigne****	****	****J.Carl Barrett****	**
**	****David Berrigan****	****	****Phil Taylor**
**	****Jennifer Eng-Wong ****	****JoAnne Zujewski**
**	****Lisa Colbert****	****	****Elaine Lanza/ Arthur Schatzkin**
**	****Volker Mai****	****	****Jeff Green/ Ron Lubet**
**	****Nomeli Nunez****	****	****Jeff Schlom/Jack Greiner**
**	****Arti Patel****	****	****DCP Biometry****	**
**M.D. Anderson Cancer Center**
**	****John DiGiovanni**
**	****Susan Fischer**
**	****Melissa Bondy****	**
**National Institute of Environmental Health Sciences**
**	****John French**
**	****Barbara Davis**
**AMC Cancer Center**
**	****Henry Thompson**