Colorectal cancer (CRC) is the UK’s second biggest cancer killer and the fourth leading cause of cancer deaths globally (www.cancer.org). Whilst established risk factors include personal or family history, studies indicate that Western dietary and lifestyle factors, particularly those that create an inflammatory environment, contribute significantly to the high incidence of CRC seen in industrialised countries. Diets rich in red and processed meat, refined starches, sugar, and saturated and trans-fatty acids but poor in fruits, vegetables, fibre, omega-3 fatty acids and whole grains are closely associated with an increased risk of CRC.
Chronic inflammation and CRC are closely linked, with the risk of developing colorectal cancer significantly increased in those individuals suffering with inflammatory bowel disease, such as ulcerative colitis and Crohn’s disease. Modifying diet to reduce systemic inflammation by manipulating the omega-6 to omega-3 ratio is believed to modify CRC risk. Here we discuss the relationship between CRC and dietary fat intake, clarifying the role of those individual fatty acids known to directly influence CRC risk.
The adenoma carcinoma sequence of CRC
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) and progression (an increase in tumour size, its spreading and acquisition of additional genetic changes). 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. 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.
Diet, gut flora and CRC
Whilst systemic factors are an important area of cancer development, the gastrointestinal tract also faces another source of genotoxicity in the form of the luminal contents. Indeed, the colonic mucosa is always exposed to the lumenal contents and therefore to any diet-related carcinogens, with a larger genotoxic burden in the colon lumen believed to directly contribute to the process of cell transformation in the initiation of carcinogenesis. Diet not only provides the substrates for the endogenous formation of carcinogens but also affects the transport and activation or deactivation of these compounds by affecting the gut flora of the large intestine and their capability to form carcinogenic metabolites. The metabolic products of fermentation, for example, directly affect genotoxicity, pH and food supply for the colonic mucosa. The products of carbohydrate fermentation (short-chain fatty acids, lactate and ethanol) have the highest concentrations within the caecum and ascending colon, whilst products of protein fermentation (ammonia, branched chain fatty acids and phenolic compounds) progressively increase from the right to the left colon, as does the pH of the lumen.As the main sources of carbon and energy for intestinal bacteria are complex carbohydrates (starches, non-starch polysaccharides) the putrefactive processes become quantitatively more important in the distal bowel, where carbohydrate is more limiting. Furthermore, it is known that the risk of colonic disorders increases from the left to the right side of the colon as the pH increases and the products of fermentation become more genotoxic. For example, ammonia, produced by bacterial hydrolysis of urea and degradation of protein entering the colon, is correlated with an increase in colonic pH, with the distal colon becoming significantly more alkaline than that of the proximal colon. The formation of n-nitroso compounds is optimum at pH 7.5, for example,and diets that are high in protein and low in fibre thereby create an environment favoured by those bacterial enzymes involved in the generation of toxic and carcinogenic metabolites from dietary and endogenously produced substances.
High fat diets and CRC risk
Dietary fat has long been hypothesised to increase the risk of developing colorectal cancer. High fat diets are known to increase 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. Diets that are rich in fibre can, however, offer protection against the potential detrimental effects of dietary fat by binding to secondary bile acids and aiding in their excretion. High dietary calcium intake is also associated with the inactivation of secondary bile acids, thereby helping to reduce the colonic cancer risk associated with high fat diets. 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. 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. Varying types of polyunsaturated fatty acids have been suggested to exert different effects on the colon in terms of promotion or inhibition of tumour development.
Polyunsaturated fatty acids, inflammation and CRC risk
The omega-6 and omega–3 polyunsaturated fatty acids are the two major classes of polyunsaturated fatty acids required for normal health that cannot be synthesised de novo by man and so must be consumed in the diet.Excessive amounts of omega-6 and a very high omega-6 to omega-3 ratio, as is found in today’s typical Western diets, promote the pathogenesis of many diseases, including cardiovascular disease, cancer, and inflammatory and autoimmune diseases, whereas increased levels of omega-3, resulting in a low omega-6 to omega-3 ratio, exert suppressive effects. 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 that regular fish consumption could reduce the risk of colorectal cancer by as much as 12%.  Experimental and clinical data have shown that omega-3 fatty acids have beneficial effects in colorectal carcinogenesis, including reduced tumour growth, suppression of angiogenesis and inhibition of metastasis. Tumour promotion requires not only the survival of initiated cells, but also their expansion. Many inflammatory mediators derived from the omega-6 fatty acid arachidonic acid (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. 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. The ratio of AA to EPA within the colic mucosa has the potential to modify the inflammatory processes which influence the development of cancer; manipulation of this ratio by dietary intervention is of increasing interest to researchers.
Cyclooxygenase (COX) enzymes and CRC
The formation of dysplastic aberrant crypt foci (ACF), the precursor to the colorectal polyp, is one of the earliest changes seen in the colon that may lead to cancer. At least four sequential genetic changes need to occur to ensure colorectal cancer evolution and the proliferating cells that are in direct contact with toxic contents of the gut lumen are highly susceptible to developing the genetic mutations necessary for development of a carcinoma.  Removal of colorectal polyps has been shown to reduce the risk of future development of colorectal cancer and advanced adenoma; methods to suppress or prevent ACF and polyp formation would therefore have a significant impact on the development of CRC. The involvement of cyclooxygenase (COX) enzymes in early colorectal tumourigenesis has seen a significant interest in the possible effects of non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin and selective cyclooxygenase-2 (COX-2) inhibitors, as interventions for protecting against CRC development. Cyclooxygenase-derived prostaglandin E2 is a known proinflammatory lipid mediator that promotes tumour progression. In animal colorectal cancer models, omega-3 fatty acids protect against colorectal cancer by inhibiting COX-2, which suppresses eicosanoid biosynthesis from AA, thereby inhibiting production of proinflammatory and tumourigenic prostaglandins and leukotrienes.
EPA as a chemopreventative agent
Common fish oil contains both EPA and docosahexaenoic acid (DHA) and whilst both are termed ‘omega-3’ the individual physiological actions of these fatty acids are continually being documented.
EPA has been shown in studies to be significantly more effective than DHA in reducing tumourigenesis in animal models of colorectal cancer,  whereas others have shown DHA to accelerate dysplastic tissue transformation.(Duriancik) It is not surprising, therefore, that the use of pure EPA, over EPA/DHA blends or indeed pure DHA, is gathering interest as a safe and potentially viable chemopreventative agent. EPA has been shown to reduce intestinal adenoma multiplicity by 79% in animal models of familial adenomatous polyposis (FAP)  and later in humans.  Indeed, when compared to placebo, the effect 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. The efficacy of EPA as a chemopreventative agent in FAP patients has prompted a larger scale randomised trial of EPA in patients with a history of colorectal adenoma undergoing colonoscopic surveillance within the English Bowel Cancer Screening Programme. Better known as the seAFOod Polyp Prevention Trial, this randomised, double blind, placebo-controlled trial, is a 2×2 factorial trial of EPA 2 g daily and aspirin 300 mg daily. Aspirin irreversibly acetylates the COX enzymes, leading to conversion of EPA to resolvin E1, which has potent anti-inflammatory activity. This ongoing trial, and collaboration with Igennus as providers of both EPA and placebo, is expected to report initial findings in 2015. 
Whilst there is a strong body of evidence supporting the anti-CRC activity of omega-3 fatty acids in in vitro and animal models, the ‘usual’ omega-3 intake via fish is generally considered inadequate to observe anti-CRC activity in humans. The potential of DHA and DHA-containing oils to exacerbate the inflammatory processes involved in tumour development has seen an explosion of pure EPA studies progressing from in vitro and use of animal models, to human phase III studies like the ongoing seAFOod Polyp Prevention Trial.
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