Cancer
That Fish You Ate Might Protect Against Colorectal Cancer
By David Kiefer, MD
Research Fellow, Department of Family Medicine, University of Wisconsin; Clinical Assistant Professor of Medicine, Arizona Center for Integrative Medicine, University of Arizona
Dr. Kiefer reports no financial relationships relevant to this field of study.
The consumption of fish, supplementation with fish oil, and their effects on cardiovascular and pain conditions are common headline-makers in the mainstream media as well as this publication. A more recent line of inquiry involves the effects of omega-3 fatty acids on tumorigenesis, cancer prevalence, and mortality. The literature on cancer, all types, is too large a scope for this article; however, taking advantage of some recently published articles, the focus here will be on the effect of dietary fish intake and, to a lesser extent, fish oil supplementation on colorectal cancer rates and associated morbidity/mortality.
Physiology
Fish and fish oil are sources of the omega-3 fatty acids (n-3), one group of fatty acids that comprise the polyunsaturated fatty acids (PUFAs).1,2,3 Furthermore, fish oils contain the long-chain omega-3 fatty acids: eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). EPA and DHA compete with arachidonic acid (AA; from omega-6 fatty acids) as substrates for metabolism by cyclooxygenase and lipoxygenase enzymes;1,4 whereas AA leads to more inflammatory cytokines through the actions of these enzymes, downstream n-3 fatty acids form series 3 prostaglandins, series 5 leukotrienes, and thromboxane A3, all of which are less inflammatory.1,3,4 This anti-inflammatory effect is one mechanism by which n-3 fatty acids are thought to be cancer protective; these less-inflammatory signaling molecules can be ligands for a number of nuclear receptors relevant to the control of the cell cycle and apoptosis.1,5 More specifically, EPA and DHA can regulate transcription factors, serving themselves as ligands of the peroxisome proliferator-activated receptors leading to antiproliferative effects in colon cancer cells.1 Another proposed mechanism is that fish oils actually might increase oxidative stress via reactive oxygen species in precancerous cells, causing them to become apoptotic.5
In addition, fish is known to contain selenium, vitamin D, and taurine in varying amounts, all of which have some proposed anti-neoplastic actions.5 The overall cancer-protective effect of fish oil, therefore, could be a combination of the effect from the n-3 fats and these micronutrients.
Some other interesting mechanisms relevant to n-3 fatty acids and cancer have been mentioned in the medical literature. For example, the anti-inflammatory effects of n-3 fatty acids that positively affect those with inflammatory bowel disease (IBD) could likewise lessen the connection between IBD and colorectal cancer.6 Also, more relevant to cancer treatment, n-3 fats may increase the antitumor effects of 5-fluorouracil (5-FU) and the radiosensitivity of colorectal adenocarcinoma cell lines.6
Preclinical Research
Expanding on the biochemical n-3 fatty acid research described above, researchers have looked at fish and fish oil as part of the diet of animals and cancer-related outcomes. The Wistar rat has been studied in this context, with an 18% fish oil diet leading to less aberrant crypt foci (ACF) and lower incidence of colorectal tumors, as well as a more recent study using 4% lipids (closer to a normolipidemic human diet) from fish oil compared to flaxseed oil, olive oil, and soybean oil.7 In this latter investigation, lower concentrations of ACF were found in the proximal colon in the fish and flaxseed oil groups (P = 0.011). Though outcomes were similar for both fish and flaxseed oil, other indications from the preclinical literature are that plant-derived n-3s are less bioactive with respect to cancer.5
Clinical Trials
The clinical trials fall into several categories, including numerous prospective cohort studies and case-control studies.6 For example, one case-control study looked at the n-3 fatty acid content of red blood cells (RBC), thought to be a more accurate representation of n-3 intake than dietary recall, in 74 incident colorectal cancer cases and 221 controls without cancer.8 The results showed no connection with dietary intakes of fish, meat, fat, or fatty acids, but colorectal cancer rates were inversely correlated with RBC DHA, AA, and PUFA content (odds ratios 0.36, 0.42, and 0.15, respectively). A predictable direct correlation between colorectal cancer and RBC saturated fatty acid content also was seen. The inverse relationship with AA was a bit of a red herring, no pun intended; AA, representative of omega-6 fatty acid intake and a competitive substrate with n-3s for the same enzyme systems, presumably would have led to increased colorectal cancer rates. The authors discuss the complicated data surrounding AA, including conflicting epidemiological evidence, and put forth a request for further research to explore the AA and colorectal connection, perhaps beyond the current paradigm.
A prospective cohort study, and one that impressively lasted 22 years using the Physicians’ Health Study data, followed 22,071 men and their fish intake and looked for correlations for 500 who had a confirmed diagnosis of colorectal cancer.9 The highest (≥ 5 times weekly) vs the lowest (< 1 time weekly) category of fish intake was inversely correlated with a lower risk of colorectal cancer (relative risk, 0.60 [0.40-0.91]). An estimate was made from the type of fish for n-3 fatty acid content, and this value also was inversely related to colorectal cancer risk (relative risk, 0.74 [0.57-0.95]). Some of the subgroup analyses bring up the complexities of doing a dietary recall study, as well as understanding the exact type of fish that is most beneficial in the context of participant demographics.
A comparable trial was undertaken in Europe, following 478,040 men and women for 4.8 years and looking for dietary correlates for the cases of colorectal cancer.10 Comparing people who consumed > 80 g of fish daily to < 10 g daily, there was an inverse relationship with colorectal cancer risk (hazard ratio, 0.69 [0.54-0.88]). The researchers found a positive relationship between red meat consumption and colorectal cancer risk; interestingly, when red meat consumption was removed as a possible confounding variable, it did not alter the association of fish consumption and decreased cancer risk.
A summary of many of the existing research trials was attempted by the authors of a recent meta-analysis.11 The authors searched for epidemiological studies (case-control or cohort studies) that explored the relationship between colorectal cancer and fresh fish consumption, finding 41 articles (22 cohort, 19 case-control). Despite the heterogeneity among the studies, there was a statistically significant trend showing a reduction in colorectal cancer risk with the highest (vs lowest or non) fish consumption (odds ratio, 0.88; confidence interval, 0.80-0.95). The authors’ calculations were that fish consumption may reduce the risk of colorectal cancer by 12%, though they were unable to comment on the quantity of fish intake necessary to reach this protective effect (due to significant heterogeneity in the methods and units of fish intake), nor to comment on the effect of fish oil supplementation or other types (i.e., salted) of fish.
Another meta-analysis considering all cancers failed to find a relationship (either positive or negative) between plant-based n-3 fats and colorectal cancer;12 however, the authors did support the fact that limited evidence exists for a protective effect of the long-chain fatty acids, DHA and EPA, on colorectal cancer risk. As with the meta-analysis described in the prior paragraph, a serious challenge to interpreting the data in this meta-analysis is the lack of homogeneity in the studies analyzed, the multifactorial aspect of colorectal cancer, and the difficulties in pinning down the exact type of fish (and resulting n-3 content) consumed. One trial reviewed in this meta-analysis may offer a view into a more simple and accurate way to address these issues; using serum n-3 fatty acid levels and an endoscopy-based, case-control approach, which in this case found an inverse relationship between serum n-3 fatty acids and colorectal adenoma risk. Some, but not universal, benefits also were seen in yet another meta-analysis, with an inverse relationship between the highest vs lowest intake of n-3 on colorectal cancer incidence (relative risk, 0.88 [0.78-1.00]), but not for colorectal cancer mortality.13 In this latter meta-analysis, when fish consumption was at least seven times monthly, the relative risk improved and became more significant. Furthermore, the authors estimate that each additional time per week that fish is consumed, or for each additional 100 g of fish eaten per week, there is a 3% or 4% lower risk of colorectal cancer, respectively.
Other trials related to colorectal cancer have looked at the effect of fish or fish oil in people already diagnosed or treated for colorectal cancer. For example, in one study, colorectal patients were given 900 mg DHA+EPA, which was found to help improve inflammatory markers and nutritional status,14 though there are unclear ramifications regarding the cancer pathophysiology itself.
Dose
In general, it is difficult to determine dose from the epidemiological research as described above, a parameter that is more convincingly established by prospective, randomized, controlled trials. That said, an optimal dose range for colorectal cancer protection can be estimated by aiming for the higher levels in the clinical trials with positive results on colorectal cancer risk. Examples would be fish consumption more than 5-7 times weekly, or more than 80 g of fish daily; 80 g of fish is approximately 3 ounces or a small fillet.
Conclusion
The connection between fish consumption and lower risk of colorectal cancer has grounds both in physiology and clinical research. Fish and fish oil, high in long-chain n-3 fatty acids, may prevent colorectal cancer through its well-known anti-inflammatory effects, as well as several direct antiproliferative effects as proposed in various cancer models. Most of the clinical research has employed either case-control or cohort methodologies, and there is general agreement that higher levels of dietary fish consumption are inversely related to a lower risk of colorectal cancer. Exact doses needed to achieve these effects remain to be determined, but extrapolation from the published research seems to indicate that almost once daily fish intake is ideal. There is debate about the type of fish and for which demographics this connection is most convincingly shown. Preliminary results seem to indicate that plant-based n-3 fats have less of a protective effect against colorectal cancer.
Recommendation
Eating fish regularly may help to lessen a person’s risk of colorectal cancer, so it should be one dietary consideration for preventing this disease process. This intervention may provide benefits regardless of other aspects of the diet, but further benefits in colorectal cancer prevention could be achieved by eating less red meat, exercising regularly, and probably eating more fiber.1,15 Given that one-half of diagnosed cases of colorectal cancer may be related to diet,11 this is an important line of investigation for researchers, clinicians, and patients alike. In most studies, n-3 fatty acid content of the ingested fish correlates with improved colorectal cancer rates, but not always, so it is unclear whether fish oil provides the same protection or how many mg of fish oil is necessary to match the benefits seen in consuming fish 5-7 times weekly. There are minimal risks associated with a recommendation to eat more cold-water fish; it is becoming increasingly important, however, to find sustainable sources of fish, as well as fish that is free of contaminants, such as mercury and PCBs, in order to meet the intake guidelines suggested by the results of recent investigations.
References
1. Pauwels EK. The protective effect of the Mediterranean diet: Focus on cancer and cardiovascular risk. Med Princ Pract 2011;20:103-111.
2. Covington MB. Omega-3 fatty acids. Am Fam Physician 2004;70:133-140.
3. Deckelbaum RJ, Torrejon C. The omega-3 fatty acid nutritional landscape: Health benefits and sources. J Nutr 2012;142:587S-591S.
4. Cleland LG, et al. The role of fish oils in the treatment of rheumatoid arthritis. Drugs 2003;63:845-853.
5. Lund EK, et al. Recent advances in understanding the role of diet and obesity in the development of colorectal cancer. Proc Nutr Soc 2011;70:194-204.
6. Sala-Vila A, Calder PC. Update on the relationship of fish intake with prostate, breast, and colorectal cancers. Crit Rev Food Sci Nutr 2011;51:855-871.
7. Rosa DD, et al. Fish oil improves the lipid profile and reduces inflammatory cytokines in Wistar rats with precancerous colon lesions. Nutr Cancer 2012;64:569-579.
8. Kuriki K, et al. Risk of colorectal cancer is linked to erythrocyte compositions of fatty acids as biomarkers for dietary intakes of fish, fat, and fatty acids. Cancer Epidemiol Biomarkers Prev 2006;15:1791-1798.
9. Hall MN, et al. A 22-year prospective study of fish, n-3 fatty acid intake, and colorectal cancer risk in men. Cancer Epidemiol Biomarkers Prev 2008;17:1136-1143.
10. Norat T, et al. Meat, fish, and colorectal cancer risk: The European Prospective Investigation into Cancer and Nutrition. J Natl Cancer Inst 2005;97:906-916.
11. Wu S, et al. Fish consumption and colorectal cancer risk in humans: A systematic review and meta-analysis. Am J Med 2012;125:551-559.e5.
12. Gerber M. Omega-3 fatty acids and cancers: A systematic update review of epidemiological studies. Br J Nutr 2012;107(Suppl 2): S228-S239.
13. Geelen A, et al. Fish consumption, n-3 fatty acids, and colorectal cancer: A meta-analysis of prospective cohort studies. Am J Epidemiol 2007;66:1116-1125.
14. Silva Jde A, et al. Fish oil supplement alters markers of inflammatory and nutritional status in colorectal cancer patients. Nutr Cancer 2012;64:267-273.
15. Barone M, et al. Dietary, endocrine, and metabolic factors in the development of colorectal cancer. J Gastrointest Cancer 2012;43:13-19.
The consumption of fish, supplementation with fish oil, and their effects on cardiovascular and pain conditions are common headline-makers in the mainstream media as well as this publication. A more recent line of inquiry involves the effects of omega-3 fatty acids on tumorigenesis, cancer prevalence, and mortality.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
- Award-winning Medical Content
- Latest Advances & Development in Medicine
- Unbiased Content