Reviewn-3 Polyunsaturated fatty acids and colon cancer prevention
Introduction
Malignant neoplasia in the colon is one of the most prevalent diagnoses in oncology. Colon cancer incidence shows regular increase of 3–7% annually and, according to latest estimates, it is responsible for over 150,000 deaths per year, mostly in industrialised countries having adopted a Western diet.1
Colon cancer develops through several stages2 (Fig. 1). The first stage is characterised by hyperplasia as a result of mutations in genes responsible for DNA repair and, sometimes, an uncontrolled hyperproliferation of colonic crypt cells. Subsequent to this, mutations in genes controlling the cell cycle (proto-oncogenes and tumour suppressor genes) may occur and lead to neoplastic clonal expansion of crypt cells. Then, intraepithelial neoplasia spreads to multiple sites of the colonic mucosa and gives rise to adenomatous polyps that remain preinvasive and premalignant at this stage. However, neoplastic cells can become invasive by crossing the basement membrane of the epithelium and making their way into other tissues. Death is usually a result of the development of metastases, particularly in the lymph nodes. This chain of events can take 5–40 years. It clearly indicates that primary prevention or, failing that, early diagnosis and prevention of secondary tumour formation should be focused upon.
Colon cancer aetiology is complex and involves both genetic and environmental factors. Genetic predispositions, such as Familial Adenomatous Polyposis, increase the risk of developing colon cancer by the age of 21. However, the prevalence of such predispositions is low and 90% of cases are due to other factors, from which 50–80% are environmental.3 Among the environmental factors, the dietary habits play a major role. Low intake of fibres, fruit and vegetables and high intake of fat have been linked with increased risk of colon cancer.4 Therefore, dietary recommendations have been established4 to encourage people to change their dietary habits, to reduce colon cancer risk and lower the burden of personal suffering and the cost of treatment.
Although there has been some emphasis on the effect of the total amount of fat in the diet,5., 6., 7. it appears that fat quality is also important in predisposing to colon cancer. For example, several studies report protective properties of n-3 polyunsaturated fatty acids (n-3 PUFAs) in the early stages of colon cancer development, raising the question of whether these fatty acids should be recommended as part of primary prevention strategy. In this article, we will review the evidence that n-3 PUFAs affect colon carcinogenesis and discuss the mechanisms by which these fatty acids act. Finally, we will discuss the different issues for or against the use of PUFAs in colon cancer prevention.
n-6 and n-3 PUFAs are named according to the position of the first double bond from the methyl terminus of the hydrocarbon chain of the molecule.8 Most of the n-6 and n-3 PUFAs are metabolised from precursors, linoleic acid (LA; 18:2n-6) and alpha-linolenic acid (ALNA; 18:3n-3), respectively, by a series of elongation and desaturation reactions to yield longer, more unsaturated fatty acids (Fig. 2). LA is converted to arachidonic acid (AA; 20:4n-6), while ALNA is converted to eicosapentaenoic acid (EPA; 20:5n-3) and docosahexaenoic acid (DHA; 22:6n-3). Mammalian organisms, unlike plants, do not possess the Δ12 and Δ15 desaturase enzymes required for LA and ALNA synthesis. Therefore, these two PUFAs are considered as essential and must be consumed in the diet in order to maintain adequate body pools. LA can be found in high proportions in many vegetable seeds and oils (safflower, soybean, coconut, corn and sunflower), while rich sources of ALNA are dark green leafy plants and perilla, linseed, rapeseed, walnut and blackcurrant seed oils. Moreover, fish oil is a good mean to supplement diet with longer PUFAs, because plankton and algae, which are at the base of the food chain for tuna, salmon, herring, etc. are rich in ALNA and longer chain n-3 PUFAs.
n-6 and n-3 PUFAs have a number of vital functions in the human body9., 10., 11., 12. as structural phospholipids of the cell membrane, they modulate membrane fluidity, cellular signalling and cellular interaction. Moreover, they play an important role in the regulation of the immune system by acting as precursors for the synthesis of eicosanoids. These potent immunoregulatory metabolites are synthesised from the 20-carbon PUFA precursors. AA or EPA are mobilised from the cell membrane by the action of phospholipase enzymes, especially phospholipase A2 (PLA2) and C (PLC), and subsequently metabolised by cyclooxygenase (COX) or lipoxygenase (LOX) enzymes into prostaglandins (PGs), thromboxanes (TXs) and leukotrienes (LTs) (Fig. 2). Because cell membrane phospholipids normally contain much higher levels of AA than of the other 20-carbon PUFAs,13 AA is the most common eicosanoid precursor and gives rise to 2-series PGs and TXs and 4-series LTs. In contrast, EPA gives rise to 3-series PGs and TXs and 5-series LTs (Fig. 2), the difference being the presence of an additional double bond in the structure.
There is competition between n-6 and n-3 PUFAs for their metabolic conversion via desaturase and elongase enzymes, which are common to both pathways (Fig. 2). However, these enzymes have a greater affinity for n-3 PUFAs,14 such that when dietary n-3 PUFA intake is high, they are preferentially metabolised. This leads to a “competitive inhibition” of n-6 PUFA metabolism, where LA desaturation and AA concentrations are significantly decreased after ALNA, EPA, or DHA supplementation.13., 15., 16. AA and EPA also compete for the COX and LOX enzymes. Since n-3 PUFAs are preferentially used, any supplementation with n-3 PUFAs (e.g. as FO) will have a considerable impact on the class of eicosanoids produced. Thus, increased intake of n-3 PUFAs results in decreased generation of AA-derived eicosanoids.17 This can be mirrored by an elevation in the generation of mediators from EPA.18 It is considered that the eicosanoids produced from EPA are less pro-inflammatory in their action than the AA-derived mediators. This is the rationale for the use of FO supplements in asthma19 and rheumatoid arthritis.20
Section snippets
Epidemiological studies
Epidemiological studies revealed a significantly lower incidence of colorectal cancer in Greenland Eskimo populations eating their traditional diet compared to reference populations in the West.21 This population consumed substantial amounts (>10.0 g/d) of long chain n-3 PUFAs (EPA, DHA and docosapentaenoic acid). In contrast, the Western diet contains approximately only 1–2 g/d of n-3 PUFAs, mostly as ALNA with long chain n-3 PUFAs contributing <0.25 g/d.11., 12. Japanese migrants to the US who
Mechanisms of action of n-3 PUFAs
During cancer development, cell turnover, differentiation and apoptosis are impaired. Many factors influence tumour induction and growth in colon cancer, including a range of cytokines and growth factors, and genotoxic and oxidative stress (Fig. 3). N-3 PUFAs are able to influence colon carcinogenesis by alterating either enzyme expression and/or activity and, therefore, the concentrations of end-products, or by modulating the levels of available precursors for biosynthetic pathways.
Effects of n-3 PUFAs on cachexia and survival
The various effects of n-3 PUFAs described above would have a considerable impact on cancer patients’ status (Fig. 5). Cachexia, the catabolic state that develops in the late stages of most cancers, is one of the main aggravating symptoms. It is present in half of untreated cancer patients and is inversely correlated to the survival.73 There is a complex interplay of cytokines and hormones that modulate cachexia. Cytokines involved include tumour necrosis factor alpha (TNF-alpha), interleukins
Potential adverse effects of n-3 PUFAs in colon cancer
Despite the wide ranging evidence from experimental and clinical studies of the potential benefit of n-3 PUFAs in colon cancer, some disturbing observations have been made. Griffini et al.82 noted that rats with an experimentally induced colon cancer involving liver metastases and fed a diet containing 20% by weight of FO had increased secondary tumour formation and developed 1000-fold more metastases than those fed a low-fat diet or a diet enriched with safflower oil. It is not clear how this
A newly emerging factor that might influence the effect of n-3 PUFAs in colon cancer: genotype
TNF-α plays an important role in inflammation and cachexia. Studies in laboratory animals, healthy human volunteers and various patient groups have indicated that n-3 PUFAs decrease the ability of mononuclear cells to produce TNF-α.20 This is a key element of the anti-inflammatory effects of FO and partly explains the efficacy of this approach in inflammatory disorders.20 However, a recent study has indicated variations in response to FO. This has been explained by a response depending on
Recommendations: insufficient evidence
At the present time, it is too early to make any recommendations regarding the use of n-3 PUFAs or their dosage in colon cancer therapy, and research should continue to investigate the potential negative effects mentioned above. The problem of secondary prevention should be approached with some caution. Nevertheless it appears that there are definite benefits in increasing the ratio of n-3 to n-6 PUFAs in the diet as a preventive strategy.11., 12. The precise ratio remains to be determined.3.,
Conclusion
n-3 PUFAs have emerged as anti-carcinogenic nutrients of potential benefit in colon cancer. They work through several actions to protect against the initiation and early stages of cancer, including decreasing tumour cell proliferation, enhancing tumour cell apoptosis, promoting cell differentiation, and limiting angiogenesis. Although, these appear to be disparate effects, they largely work through a limited range of mechanisms including competitive inhibition of AA metabolism and alteration of
Acknowledgements
We acknowledge Nutrition 2000 Foundation for its financial support.
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