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Lifestyle and prevention
of colon cancer
Clara Natoli, Chieti
Age-standardized incidence of colorectal cancer
in the world (per 100,000 individuals)
From the International Agency for Research on Cancer, Lyon, France Cancer. Microenviron. 2011 August; 4(2): 133–139
Trends in Incidence Rates for Selected Cancers by
Sex, United States, 1975 to 2008
CA CANCER J CLIN 2012;62:10–29
CA CANCER J CLIN 2012;62:10–29
CA CANCER J CLIN 2012;62:10–29
1970’s
23 COUNTRIES WITH HIGH AND LOW CANCER RATES
• The more animal products people consumed,
the greater their risks of colorectal, breast,
ovarian and prostate cancer
• The more fruits, vegetables, whole grains and
fish people consumed, the lower their risks of
cancer
• People who migrated took on the cancer risk of
the country to which they migrated
DOLL AND ARMSTRONG, INT J CANCER, 1975:15, 617
CRC Risk Factors
 unmodifiable risk factors
 modifiable risk factors
Unmodifiable CRC Risk Factors
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•
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Age
African-American race
Diabetes
HNPCC – Lynch syndrome I, II
Polyposis syndromes – FAP, Gardner’s syndrome,
Turcot’s syndrome, juvenile polyposis
• Inflammatory bowel disease – chronic ulcerative colitis,
Crohn’s disease
Modifiable CRC risk factors
Dietary factors
– Red meat, high animal fat, low fiber diet
 Lifestyle
– Sedentary
– Obesity
– Smoking
– Alcohol
may account for up to 70% of colorectal cancers!
Exercise and CCR Risk
• 43 out of 51 studies demonstrated decreased risk
of colon cancer in the most physically active
participants
• Risk reduction averaged 40%-50%, up to 70%
• Consistent risk reduction despite differing study
designs and populations and types of exercise
• Greater effect in men vs. women
• Unclear exercise effect on rectal cancer
Bernstein L, AACR Education Book 2008:225-231 (2008)
Friedenreich CM, et al. J Nutr 132:3456-3464, 2002.
Colonic findings according
to exercise history
at least one hour of
weekly exercise
Sanchez et al. BMC Research Notes 2012, 5:312
Exercise and CCR Survival
 3h per week of moderate physical activity after
colon cancer diagnosis:
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

39%-59% decreased risk of colon cancer death
50%-63% decreased risk of total death
Effect essentially unchanged across age, sex, BMI,
disease stage, age at diagnosis
Meyerhardt JA, et al. J Clin Oncol 2006;24:3535–41
Methods of measuring obesity
C. L. Donohoe et al, British Journal of Surgery 2010; 97: 628–642
Forest plot of odds ratios of colorectal
adenomas according to BMI
Am J Gastroenterol 2012; 107:1175– 1185; doi: 10.1038/ajg.2012.180; published online 26 June 2012
Incidence of invasive CRC according to behavioral risk factors and MBI
Howard RA et al, Cancer Causes Control. 2008 Nov;19(9):939-53
Mortality from cancer
according to body mass index
British Journal of Surgery 2010; 97: 628–642
Definitions of metabolic syndromes
Cancer Prev Res; 4(11) November 2011
Forest plot of odds ratios of CRC
according to metabolic syndrome
Metabolic Syndrome and Risk of Cancer: A Systematic Review and
Meta-Analysis
Diabetes Care 35:2402–2411, 2012
Forest plot of odds ratios of CRC
according to metabolic syndrome
Diabetes Care 35:2402–2411, 2012
Unhealthy lifestyles and their
health consequences, such as
obesity, affect molecular
pathways involved in colorectal
carcinogenesis
The Anatomy of the Colon
Differentiated
cells
Transitamplifying
cells
Stem cell
niche
Tumor Promotion in the Colon
Initiation
Promotion
Progression
Activated
Myofibroblast
HGF
Myofibroblast
Myeloid cells
IL-6 TNFa
Normal organization of
the intestinal crypt
Loss of wild-type APC or
β-catenin mutation.
Transformation of healthy
crypts towards an adenoma
Accumulation of other genetic
lesions, RAS and PTEN.
Progression towards an invasive
growing CRC
Stem cell concept in CRC development
This pathway is believed to be
operational in most sporadic cases
of colorectal carcinoma and in
FAP.
Inherited syndromes leading to
CRC have helped to identify the
genetic basis of sporadic CRC
Familial Adenomatous Polyposis (FAP)
• Germline mutations of APC gene, a gatekeeper tumor
suppressor, that functions in Wnt signal transduction
pathway
• APC mutated in 70% sporadic CRCs
• “APC tumor pathway” characterized by chromosomal
instability, aneuploidy and loss of heterozygosity for
tumor suppressor genes
APC protein
Multiple 20-amino acid repeats that mediate binding to b-catenin and axin are in middlethird of protein. Mutations (germ-line and somatic) result in protein truncation.
Fearon ER, Annu Rev Pathol Mech Dis 6:479-507, 2011
Model of adenomatous polyposis coli
(APC) and β-catenin function
destruction complex
TCF-regulated target genes
Fearon ER, Annu Rev Pathol Mech Dis 6:479-507, 2011
Role of APC in regulating b-catenin
In the absence of WNT signaling (A) APC causes degradation of b-catenin. Signaling by
WNT (B) deactivates the APC complex allowing b-catenin to translocate to nucleus.
Mutations of APC (C) leads to continuous WNT signaling.
Fearon ER, Annu Rev Pathol Mech Dis 6:479-507, 2011
Lynch syndrome
 Germline mutations of hMLH1 (50%), hMSH2 (40%),
hPMS1, hPMS2, hMSH6, caretaker tumor suppressors
that function in DNA mismatch repair (MMR)
 Note: inactivation of hMLH1 (by methylation) in 15% of
sporadic CRCs
 Characterized by microsatellite instability (MSI-H) and
hypermutable phenotype
Human DNA mismatch repair (MMR)
hMLH1 functions as a ‘molecular matchmaker”, coupling DNA strand recognition
with downstream repair.
Fearon ER, Annu Rev Pathol Mech Dis 6:479-507, 2011
Relative effects of mutation in promoting tumor
initiation and progression
“tumor of initiation”
“tumor of progression”
How diet impacts cancer risks
 Insulin/IGF-1
 Free radicals/antioxidants
 Detoxification enzymes
 DNA repair
Conceptual model of the relationships among socioeconomic
factors, health behaviors and colorectal cancer risk
Doubeni C A et al. JNCI J Natl Cancer Inst 2012;104:1353-1362
Metabolic roles of adipose tissue in obese patients
C. L. Donohoe et al, British Journal of Surgery 2010; 97: 628–642
Mechanisms linking obesity with CRC
E. Yehuda-Shnaidman and B. Schwartz, obesity reviews (2012) doi: 10.1111/j.1467-789X.2012.01024.x
Dysfunctional adipose tissue
E. Yehuda-Shnaidman and B. Schwartz, obesity reviews (2012) doi: 10.1111/j.1467-789X.2012.01024.x
Obesity and cancer risk
Caloric restriction
decrease leptin, insulin,
IGF-1, proinflammatory
cytokines
Obesity
increased leptin, insulin,
IGF-1, proinflammatory cytokines
+
-
PI3K/
Akt
+
mTOR
-
AMPK
+
Cancer proliferation and survival
Annals of the New York Academy of Sciences
Volume 1271, Issue 1, pages 37-43, 10 OCT 2012
Translating prevention
Cancer
Prevention
The Polyp Prevention Trial (PPT)
Multicenter randomized controlled trial examining the effect of a
low-fat (20% of total energy intake),
high-fiber (18 g/1000 kcal),
high-vegetable and -fruit (5-8 daily servings) dietary pattern
on the recurrence of adenomatous polyps of the large bowel
Eligibility
one or more adenomas removed within 6 months
complete nonsurgical polyp removal
complete colonic examination
age 35 years or older;
no history of colorectal cancer, inflammatory bowel disease, or large bowel resection;
satisfactory completion of a food frequency questionnaire and 4-day food record
This study failed to show any effect of a low-fat, high-fiber, high-fruit and
-vegetable eating pattern on adenoma recurrence even with 8 years of
follow-up.
Cancer Epidemiol Biomarkers Prev 2007;16(9):1745-52
A randomised controlled trial, designed to measure the impact of
a body weight and physical activity intervention on adults at risk
of developing colorectal adenomas
The focus of the BeWEL intervention is based on evidence of an
association between physical activity, obesity, and diet and risk of
CRC and other chronic diseases and that approximately 43% of
CRC can be prevented through changes in these risk factors
Stead M et al, Preventive Medicine (in press) doi:10.1016/j.ypmed.2011.10.017.
 All patients were advised of the study through a letter of introduction
 This letter was then followed two weeks later by a written invitation
from the research team. Those interested were telephone
screened for BMI (> 25 kg/m2) and availability.
 A discussion guide was developed containing open-ended questions
around key areas including experiences of adenoma diagnosis
and treatment, understanding of adenoma and its relationship
to lifestyle and disease, and how participants would feel about
being offered advice and support for making behaviour
changes, particularly in relation to healthy eating, physical
activity and weight loss.
 Focus groups were moderated by an experienced researcher and
digitally audio-recorded with participants' consent.
Stead M et al, Preventive Medicine (in press) doi:10.1016/j.ypmed.2011.10.017.