Title: Colorectal cancer

Key words: large bowel, dietary fibre, genetic basis, APC, Crohn's disease, ulcerative colitis, risk factors, anti-inflammatory drugs, NSAIDs, FOS, prebiotics, smokers, folate deficiency, probiotics,

Date: June 2001

Category: Specific conditions

Type: Article

Author: Dr M Draper


Colorectal cancer


Colorectal cancer is the second most common cancer in western societies, affecting up to 6% of men and women by the age of 75 (1). The strong evidence that the majority of large bowel cancers are attributable to environmental factors suggests that it is a potentially preventable disease. An early, epidemiologically-based hypothesis proposed by Burkitt was that the up-to-10-fold higher UK incidence compared to Africa (2) was due to dietary fiber has proved to be incorrect (3) Indeed, no protective effect has been shown for fibre in recurrence of colorectal adenomas (4,5). More recent suggestions to explain these differences include higher intakes of non-starch polysaccharides, salicylate and lower meat intakes in Africa.

Genetic basis of colorectal cancer:

Various genetically determined conditions (Familial Adenosis Polyposis 1%, Hereditary non-polyposis Cancer 2-4%, Familial 5%) account for up to 15% of colorectal cancers. 85% of cases have no obvious genetic basis. However the cells of many colon cancers have the wrong number of chromosomes, as well as defects in a protein called APC (adenomatous polyposis coli [6]). The current working hypotheses revolve around the mutagenic effects that arise if the gatekeeper APC is defective or the Cox-2 enzyme upregulated. The APC protein is a tumour suppressor (7) and this is linked intimately to its participation in the efficient turnover of B-catenin and to the Wnt signaling pathway. APC's putative functions include; cell adhesion, signal transduction, apoptosis, and cell cycle regulation. Mouse studies have delineated the critical domains (8). Familial colorectal cancer in Ashkenazim is due to a hypermutable APC (9). Zinc is protective against mutagenesis probably through zinc fingers which repair damaged DNA.

Pharmaceutical and dietary influences:

Anti-inflammatories (NSAIs)(10) and Aspirin (11,12) reduce the risk of colon cancer. The Aspirin effect is dose dependent and death rates decreased with more frequent usage in men and women. The relative risk when 16 or more ASA doses are taken per month for at least one year was 0.6 in men. Aspirin is a Cox -2 inhibitor. Fybogel may increase the risk of colorectal cancer (GR5). Folate (13) and Acetylator status (14) also appear to be protective. A new observation is that slow acetylators who smoke may be more at risk of colon cancer. Inflammatory conditions such as Crohn's disease and ulcerative colitis cause an increased risk of developing colorectal cancer. In ulcerative colitis, incidence can be a two fold increase over the normal population. Increased risk factors include long duration of the disease, low activity of the disease, folate deficiency and inadequate pharmacological therapy (usually anti-inflammatory drugs such as salazopyrine). Various mutagenic changes have been noted (15) and the bowel flora are often abnormal.

The colonic mucosa derives most of its nutrition from the lumen (16) and localised Bifidobacteria are often credited with the protective effect. Lactobacillus species can produce nutrients (17), eliminate toxic components (18) and eradicate pathogenic species. Prebiotics such as fructo-oligo saccharides (FOS) and inulin are resistant to the enzymes of the small intestine and stimulate Bifidobacteria. The average diet in the UK provides 2gms of resistant starches and it is estimated that the African diet involves intakes of 4-8 gms per day. The protective effect of dietary FOS or inulin has been demonstrated by inhibition of colonic preneoplastic aberrant crypt formation (19).

Conclusion A multicentre study (GR5) with 4 groups: placebo, FOS, ASA 600mgs per day and both FOS & ASA will, hopefully, clarify these relationships.

References (1) Bingham, S.A. (1996) ' Epidemiology and mechanisms relating diet to risk of colorectal cancer.' Nutr Res Rev 9: 197-239.

(2) Segal, I. et al. (2000) ' Continuing low colon cancer incidence in African populations ' Am J Gastroenterol , 200004, 95: 4, 859-60.

(3) Fuchs, C.S. (1999) ' Dietary fiber and the risk of colorectal cancer and adenoma in women.' N Engl J Med 340: No3; 169-176.

(4) Alberts, D.S. et al. (2000) ' Lack of effect of high-fiber cereal supplement on the reoccurrence of colorectal adenomas.' N Engl J Med. 342: 1156-62.

(5) Bonithon-Kopp, C. et al. (2000) ' Calcium and fibre supplementation in prevention of colorectal adenoma recurrence: a randomised intervention trial.' Lancet 356: 1300-06.

(6) Livingston, D.M. (2001) ' Chromosome defects in the colon.'

Nature Vol 410 536-537.

(7) Polakis, P. (1997) ' The adenomatosis polyposis coli (APC) tumour suppressor.' Biochemica et Biophysica Acta 1332: F127-147.

(8) Smits, R. et al. (1999) ' Apc1638T: a mouse model delineating critical domains of the adenomatosis polyposis protein involved in tumorigenesis and development.' Genes & Development 13: 1309-1321.

(9) Giardiello, F.M. et al. (1997) ' Familial colorectal cancer in Ashkenazim due to a hypermutable tract in APC.' Nature Genetics Vol 17: 79-83.

(10) Marx, J. (2001) ' Anti-inflammatories inhibit Cancer Growth - but How ?' Science 291: 581-2.

(11) Thun,M.J. et al. (1991) 'Aspirin use and reduced risk of fatal colon cancer' N Engl J Med 325, No 23: 1593-6

(12) Ruscchoff,J. et al. (1998) ' Aspirin suppresses the mutator phenotype associated with hereditary nonpolyposis colorectal cancer by genetic selection.' Proc Natl Acad Sci 95: 11301-6.

(13) Ma, J. et al. (1997) ' Methylenetrahydrofolate Reductase Polymorphism, Dietary interactions and Risk of colorectal cancer.' Cancer Research 57:1098-1102.

(14) Welfare, M.R. et al. (1997) ' Relationship between acetylator status, smoking and colorectal cancer risk in the north-east of England.' Carcinogenesis vol 18, no 7:1351-1354.

(15) Pohl, C. et al. (2000) 'Chronic inflammatory bowel disease and cancer.' Hepatogastroenterology, 200000, 47: 31, 57-70.

(16) Bengmark, S. (2000) ' Colonic food: pre and pro-biotics. ' Am J Gastroentol, 200001, 95: 1 Suppl, S5-7.

(17) Hague,A. et al.(1993) ' Sodium butyrate induces apotosis in human colonic tumour cell lines in a p53-independent pathway.' Int J Cancer %%: 498-505.

(18) Hayasu, H. & Hayatsu, T. (1993) ' Suppressing effect of Lactobacillus casei administration on the urinary mutagenicity arising from ingestion of fried ground beef in the human.' Cancer Lett. 73: 167-172.)

19) Reddy, B.S. et al. (1997) ' Effect of dietary oligofructose and inulin on colonic preneoplastic aberrant crypt foci inhibition.' Carcinogenesis Vol 18 no7: 1371-1374.

General References:

(1) Trends in Patterns of Disease and Diet: Fact File No 10: 1993 National Dairy Council. London.

(2) Food, Nutrition and the Prevention of cancer: a global perspective.1997 World Cancer Research Fund.

(3) Department of health 1998 .Nutritional aspects of the Development of Cancer. Report of the Working group on Diet and Cancer of the Committee on Medical Aspects of Food and Nutrition Policy. No 48. London HMSO.

(4) Doll, R. & Peto, R (1981) ' The causes of cancer: quantative estimates of avoidable risks of cancer in the United States today.' J Natl Cancer Inst.66:1191-1308.

(5) Mathers, J. (2001) MSc University of Surrey Lecture Module 5 lecture notes.