1. Lifestyle and prevention of colon cancer Clara Natoli, Chieti

2. From the International Agency for Research on Cancer, Lyon, France Cancer. Microenviron. 2011 August; 4(2): 133–139 Age-standardized incidence of colorectal cancer in the world (per 100,000 individuals)

3. CA CANCER J CLIN 2012;62:10–29 Trends in Incidence Rates for Selected Cancers by Sex, United States, 1975 to 2008

4. CA CANCER J CLIN 2012;62:10–29

9. 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

10. unmodifiable risk factors modifiable risk factors CRC Risk Factors

11. 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 Unmodifiable CRC Risk Factors

12. Dietary factors –Red meat, high animal fat, low fiber diet Lifestyle –Sedentary –Obesity –Smoking –Alcohol Modifiable CRC risk factors may account for up to 70% of colorectal cancers!

13. 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.

14. Sanchez et al. BMC Research Notes 2012, 5:312 Colonic findings according to exercise history at least one hour of weekly exercise

15. Exercise and CCR Survival 3h per week of moderate physical activity after colon cancer diagnosis:  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

16. C. L. Donohoe et al, British Journal of Surgery 2010; 97: 628–642 Methods of measuring obesity

19. 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

20. Incidence of invasive CRC according to behavioral risk factors and MBI Howard RA et al, Cancer Causes Control. 2008 Nov;19(9):939-53

21. Mortality from cancer according to body mass index British Journal of Surgery 2010; 97: 628–642

22. Cancer Prev Res; 4(11) November 2011 Definitions of metabolic syndromes

23. Forest plot of odds ratios of CRC according to metabolic syndrome Diabetes Care 35:2402–2411, 2012 Metabolic Syndrome and Risk of Cancer: A Systematic Review and Meta-Analysis

24. Forest plot of odds ratios of CRC according to metabolic syndrome Diabetes Care 35:2402–2411, 2012

25. Unhealthy lifestyles and their health consequences, such as obesity, affect molecular pathways involved in colorectal carcinogenesis

26. Stem cell niche Transit- amplifying cells Differentiated cells The Anatomy of the Colon

27. 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 Myofibroblast Activated Myofibroblast HGF Myeloid cells IL-6 TNF  Progression Initiation Promotion Tumor Promotion in the Colon

28. Stem cell concept in CRC development

29. 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

30. 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

31. APC protein Fearon ER, Annu Rev Pathol Mech Dis 6:479-507, 2011 Multiple 20-amino acid repeats that mediate binding to  -catenin and axin are in middle- third of protein. Mutations (germ-line and somatic) result in protein truncation.

32. Model of adenomatous polyposis coli (APC) and β-catenin function Fearon ER, Annu Rev Pathol Mech Dis 6:479-507, 2011 destruction complex TCF-regulated target genes

33. Role of APC in regulating  -catenin Fearon ER, Annu Rev Pathol Mech Dis 6:479-507, 2011 In the absence of WNT signaling (A) APC causes degradation of  -catenin. Signaling by WNT (B) deactivates the APC complex allowing  -catenin to translocate to nucleus. Mutations of APC (C) leads to continuous WNT signaling.

34. 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

35. 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

36. Relative effects of mutation in promoting tumor initiation and progression “tumor of initiation” “tumor of progression”

37. How diet impacts cancer risks Insulin/IGF-1 Free radicals/antioxidants Detoxification enzymes DNA repair

38. 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

39. C. L. Donohoe et al, British Journal of Surgery 2010; 97: 628–642 Metabolic roles of adipose tissue in obese patients

40. Mechanisms linking obesity with CRC E. Yehuda-Shnaidman and B. Schwartz, obesity reviews (2012) doi: 10.1111/j.1467-789X.2012.01024.x

41. Dysfunctional adipose tissue

42. Obesity and cancer risk Annals of the New York Academy of Sciences Volume 1271, Issue 1, pages 37-43, 10 OCT 2012 PI3K/ Akt AMPK mTOR Cancer proliferation and survival Obesity increased leptin, insulin, IGF-1, proinflammatory cytokines Caloric restriction decrease leptin, insulin, IGF-1, proinflammatory cytokines +- - + +

45. Cancer Prevention Translating prevention

46. 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

47. 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.d

48. 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/m 2 ) 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. MESSAGE Health professionals and researchers need to encourage participants to look ahead to opportunities for health gain Stead M et al, Preventive Medicine (in press) doi:10.1016/j.ypmed.2011.10.017.