Diet and colorectal cancer risk

Nina BaileyBSc (hons) MSc PhD ANutr

Colorectal cancer is the third most common cancer in the UK after breast and lung cancer, with approximately 40,000 new cases registered each year

Colorectal cancer is the second most common cause of cancer death in the UK

Occurrence is strongly related to age, with almost three-quarters of cases of colorectal cancer occurring in people aged 65 or over

It is estimated 50% of CRC cases could be avoided by improving diet and increasing physical activity (World Cancer Research Fund, 2009)

The adenoma-carcinoma sequence

Carcinogenesis is recognised as a multi-step process involving a combination of events at the cellular, molecular and morphological levels pertaining to:

initiation (stable genomic alterations)

promotion (proliferation of genetically altered cells)

progression (an increase in tumour size, its spreading and acquisition of additional genetic changes)

The adenoma-carcinoma sequence

The genetic changes in the malignant transformation process of the colorectal mucosa include deletions, rearrangements and mutations leading to either the activation or inactivation of specific target genes including oncogenes (k-ras); tumour suppressor genes (APC, p53, DCC) and mismatch repair (MMR) genes

Thus colorectal carcinogenesis sees the normal colonic mucosa converted into a hyperproliferative state, leading to clonal expansion, formation of an adenoma eventually leading to carcinoma

Screening should begin at age 50, unless there is a family history of colon cancer, in which case it should begin earlier

Faecal occult blood test (FOBT)Stool samples tested for presence of blood

SigmoidoscopyViews lower third of the colon

Colonoscopy Views entire colon

Colonoscopy should be done every ten years, Sigmoidoscopy and FOBT every five years

The gastrointestinal tract undergoes a constant and rapid renewal and is exposed to a hostile environment from both the systemic circulation and from direct contact with the toxic content of the gut lumen

Earliest lesions in the development of adenomas are dysplastic aberrant crypt foci

The morphogenesis of adenomas is not clearly understood"top-down" vs "bottom-up“

The progression from adenoma to carcinoma can take several decades

Proximal/ascending colon

Active site ofcarbohydrate fermentation

Rapid transit

Low pH (c.a. 5.5/6.0)

Distal/descending colon

Active site of protein fermentation

Slow transit

Neutral pH ≥ 7.0

Transverse colon

Slower fermentation rate

Reduced substrate availability

Dietary fat and CRC

High fat diets have long been hypothesised to increase the risk of developing colorectal cancer, in part by increasing the secretion of bile acids, which have a nonspecific irritant effect on the colonic lumen and the production of genotoxic secondary bile acids, the metabolic by-products of intestinal bacteria linked to hyperproliferation of the colorectal mucosa

Whilst high fat diets are generally associated with increased proliferation in the large bowel, it is the role of individual fatty acids, rather than of total fat intake, that appears to be significant when addressing CRC risk

Dietary fat and CRC

Diets that are high in saturated fats, for example, are thought to increase the risk of cancer, whereas diets high in polyunsaturated fats that are rich in omega-3 fatty acids derived from fish and fish oil are thought to decrease the risk of cancer

Several studies indicate that whilst diets high in lard, beef tallow or corn oil increase the concentration of colonic luminal secondary bile acids, dietary fish oil at high concentrations have no such enhancing effect (Bartram et al., 1998)

Dietary omega-6-PUFAs can promote carcinogenesis and can increase chemically induced colonic tumours in rats, whereas diets rich in omega-3 tend to have an anti-promotional effect

Changes in omega fatty acids within the mucosa of CRC patients

Patients with CRC have shown increased concentrations of AA and AA derived prostaglandins within the tumoural mucosa (Bennett et al, 1987)

Phospholipase A2 and prostaglandin E2 (potent tumour promoter) have been shown to be increased in human colorectal cancer tissue (Soydan et al., 1996) Patients with CRC have shown increased concentrations of AA and DHA (Neoptolemos et al., 1991)

Unlike EPA, DHA may have detrimental effects on CRC by accelerating dysplastic tissue transformation (Woodworth et al., 2010)

Changes of the mucosal omega-3 and omega-6 fatty acid status occur early in the colorectal adenoma-carcinoma sequence (Fernandez-Banares et al., 1996)

Plasma fatty acidsNo difference between controls and adenoma groups

Cancer patients had significantly increased values of SFA and lower EPA compared with both controls and adenoma groups

Colonic mucosaStepwise reduction in EPA from benign adenoma to more advanced carcinoma (Dukes’ B to Dukes’ C-D)

Corresponding increase in the AA to EPA ratio

Low UI (unsaturation index) increase in SFA and decrease in MUFA

The AA to EPA ratio, inflammation and CRC

Inflammation creates the ideal “tumour microenvironment” and is now widely recognised as an enabling characteristic of cancer in regard to enhanced cell proliferation, cell survival, cell migration and angiogenesis

Many inflammatory mediators derived from AA such as cytokines, chemokines, and eicosanoids are capable of stimulating the proliferation of both untransformed and tumour cell proliferation

EPA, a key omega-3 fatty acid found in fish and fish oils possesses both anti-inflammatory and anticancer activities, giving rise to end products that directly oppose the actions of AA

The ratio of AA to EPA within the colic mucosa has the potential to modify the inflammatory processes which influence the development of cancer

Influence on transcription factor activity, gene expression, and signal transduction

Omega-3 and their metabolites may exert some of their antitumour effects by affecting gene expression or the activities of signal transduction molecules involved in the control of cell growth, differentiation apoptosis, angiogenesis and metastasis:

•Peroxisome proliferator-activated receptor (PPAR) •Nuclear transcription factor B•Ras and protein kinase C•Ornithine decarboxylase•(HMG-CoA) reductase•Cyclooxygenase-2 and lipoxygenases •Phospholipase A2

Increased or decreased production of free radicals and reactive oxygen species

Free radicals and reactive oxygen species (ROS) produced in cellsmay attack PUFAs to form lipid hydroperoxides, which leads to the formation of more free radicals and reactive aldehydes such as trans-4-hydroxy-2-nonenal and malondialdehyde

These metabolites potentially generate DNA adducts in human cells, which, if not repaired, have the potential to lead to cancer

Although omega-6 fatty acids augment these events through the overproduction of AA-derived proinflammatory eicosanoids, the omega-3 fatty acids suppress inflammation and thus the overproduction of free radicals and carcinogenesis

Bruce WR, Giacca A, Medline A: Possible mechanisms relating diet and risk of colon cancer. Cancer Epidemiol Biomarkers Prev 2000, 9(12):1271-1279.

Fish consumption and CRC risk

Oily fish is a primary source of omega-3 fatty acids and a 2012 meta-analysis of 22 prospective cohort and 19 case-control studies showed a 12% decrease in the relative risk (RR) of colorectal cancer (RR: 0.88; 95% CI: 0.78, 1.00) in a comparison of high fish consumption with low fish consumption (Wu et al., 2012)

Dietary omega-3 exposure may not be sufficient for consistent anti-CRC activity in individuals consuming moderate amounts of fish (a portion of oily fish 2–3 times per week only provides the equivalent of approximately 500 mg per day of EPA and DHA combined)

Fish or supplements?

EPA has been shown in studies to be significantly more effective than DHA in reducing tumourigenesis in animal models of colorectal cancer,with some indication that DHA may actually accelerate dysplastic tissue transformation (Petrick et al., 2000; Woodworth et al., 2010)

Increasing numbers of studies are focusing on pure EPA as a safe and potentially viable chemopreventative agent for the treatment of CRC

EPA has been shown to reduce intestinal adenoma multiplicity by 79% in animal models of familial adenomatous polyposis (FAP) (Fini et al., 2010)

In humans, the effects of EPA (2g daily for 6 months) on rectal polyp growth in patients with FAP produced a 22.4% decrease in adenoma numbers and a 29.8% reduction in adenoma size (West et al., 2010)

The seAFOod Polyp Prevention Trial (Hull et al., 2013)

The seAFOod Polyp Prevention Trial is a randomised, double-blind, placebo-controlled, 2×2 factorial ‘efficacy’ study, which will determine whether EPA prevents colorectal adenomas, either alone (1 g twice daily) or in combination with aspirin (300mg daily)

EPA and aspirin are both potent inhibitors of COX-1 but they alter COX-2 activity in ways leading to production of different bioactive lipid mediators, including PGE3 (EPA) and 15R-HETE (aspirin)

Aspirin belongs to a group of drugs called NSAIDs (Non Steroidal Anti Inflammatory Drugs) that inhibit (COX) enzymes resulting in decreased prostaglandin synthesis.

There are two isoforms of COX, COX-1 which is constitutively expressed and COX-2 which is inducible.

In colorectal carcinogenesis there is over expression of COX-2 enzyme

The seAFOod Polyp Prevention Trial

Aspirin irreversibly acetylates the COX enzymes leading to conversion of EPA to 18R-hydroxyeicosapentaenoic acid (18R-HEPE) and then trihydroxy-EPA, also known as resolvin E1, which has potent anti-inflammatory activity

Participants are 55–73 year-old patients, who have been identified as ‘high risk’ (detection of ≥5 small adenomas or ≥3 adenomas with at least one being ≥10 mm in diameter) at screening colonoscopy in the English Bowel Cancer Screening Programme (BCSP)

The primary aim of the seAFOod Polyp Prevention Trial is to determine whether the naturally-occurring EPA, prevents colorectal adenomas, either alone or in combination with aspirin

The primary end-point is the number of participants with one or more adenomas detected at routine one-year colonoscopy

Secondary end-points include the number of adenomas (total and ‘advanced’) per patient, the location (left versus right colon) of colorectal adenomas and the number of participants re-classified as ‘intermediate risk’ for future surveillance

Exploratory end-points include levels of bioactive lipid mediators such as omega-3 resolvin E1 and PGE in plasma, urine, erythrocytes and rectal mucosa in order to gain insights into the mechanism(s) of action of EPA and aspirin, alone and in combination

Summary

Western dietary and lifestyle factors, particularly those that create an inflammatory environment, contribute significantly to CRC risk

Diets that are high in omega-6 increase CRC risk, whilst diets that are rich in long-chain omega-3 may reduce the risk of developing CRC

Specifically a high AA to EPA ratio and low EPA is found within the tumour mucosa and may play a role in driving carcinogenesis

Modifying diet to reduce systemic inflammation by manipulating the AA to EPA ratio has the potential to modify CRC risk

Pure EPA, because of its safety and known anti-cancer benefits is now entering phase III human trials as a chemopreventive agent

ninab@igennus.comwww.igennus.comdrninabailey.co.uk0044 1223 421434

References

Ajouz H, Mukherji D, Shamseddine A: Secondary bile acids: an underrecognized cause of colon cancer. World J Surg Oncol 2014, 12:164.

Welberg JW, Kleibeuker JH, Van der Meer R, Kuipers F, Cats A, Van Rijsbergen H, Termont DS, Boersma-van Ek W, Vonk RJ, Mulder NH et al: Effects of oral calcium supplementation on intestinal bile acids and cytolytic activity of fecal water in patients with adenomatous polyps of the colon. Eur J Clin Invest 1993, 23(1):63-68.

Wu S, Feng B, Li K, Zhu X, Liang S, Liu X, Han S, Wang B, Wu K, Miao D et al: Fish consumption and colorectal cancer risk in humans: a systematic review and meta-analysis. Am J Med 2012, 125(6):551-559 e555.

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Wang D, DuBois RN: An inflammatory mediator, prostaglandin E2, in colorectal cancer. Cancer J 2013, 19(6):502-510.

Petrik MB, McEntee MF, Johnson BT, Obukowicz MG, Whelan J: Highly unsaturated (n-3) fatty acids, but not alpha-linolenic, conjugated linoleic or gamma-linolenic acids, reduce tumorigenesis in Apc(Min/+) mice . J Nutr 2000, 130(10):2434-2443.

Woodworth HL, McCaskey SJ, Duriancik DM, Clinthorne JF, Langohr IM, Gardner EM, Fenton JI: Dietary fish oil alters T lymphocyte cell populations and exacerbates disease in a mouse model of inflammatory colitis . Cancer Res 2010, 70(20):7960-7969.

Fini L, Piazzi G, Ceccarelli C, Daoud Y, Belluzzi A, Munarini A, Graziani G, Fogliano V, Selgrad M, Garcia M et al: Highly purified eicosapentaenoic acid as free fatty acids strongly suppresses polyps in Apc(Min/+) mice . Clin Cancer Res 2010, 16(23):5703-5711.

West NJ, Clark SK, Phillips RK, Hutchinson JM, Leicester RJ, Belluzzi A, Hull MA: Eicosapentaenoic acid reduces rectal polyp number and size in familial adenomatous polyposis. Gut 2010, 59(7):918-925.

Hull MA, Sandell AC, Montgomery AA, Logan RF, Clifford GM, Rees CJ, Loadman PM, Whitham D: A randomized controlled trial of eicosapentaenoic acid and/or aspirin for colorectal adenoma prevention during colonoscopic surveillance in the NHS Bowel Cancer Screening Programme (The seAFOod Polyp Prevention Trial): study protocol for a randomized controlled trial. Trials 2013, 14(1):237. 

Alteration of oestrogen metabolism

Oestrogen has proliferative effects on oestrogen-sensitive tissues and high oestrogen concentrations may increase the risk of breast cancer and of some other hormone-dependent cancers

AA-derived eicosanoid PGE2 has been shown to stimulate the activity of aromatase P450, which converts 19-carbon steroids to oestrogens

PGE3, a product of EPA metabolism, does not activate aromatase P450

Increasing EPA intake leads to increased PGE3 and a decrease in PGE2 from AA, thereby decreasing oestrogen production and reducing oestrogen-stimulated cell growth