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Dairy products and colorectal cancer. A review of possible mechanisms and epidemiological evidence

Abstract

Objective: This review provides an overview of the principal hypotheses and epidemiological evidence of the possible links between colorectal cancer and intake of milk and/or dairy products.

Methods: The first section outlines the main hypotheses about the possible effect of calcium, vitamin D, fats and other milk components. The possible role of acid lactic bateria in fermented products is also discussed. The second section is a summary of the published epidemiological evidence. The results on milk, cheese and yoghurt are summarized using a meta-analytical approach. The results of studies on calcium and vitamin D are briefly described.

Results: Case–control studies are heterogeneous and, on average, do not provide evidence of association between total intake of total dairy products, milk, cheese or yoghurt and colorectal cancer risk. The average result from cohort studies support the hypothesis of a protective effect of total dairy products (odds ratio (OR): 0.62; 95% confidence interval (CI): 0.52–0.74; P heterogeneity test: 0.93) and for milk (OR: 0.80; 95% CI: 0.68–0.95; P heterogeneity: 0.77). No association was found between cheese (OR: 1.10; 95% CI: 0.88–1.36; P heterogeneity: 0.55) or yoghurt (OR: 1.03; 95% CI: 0.83–1.28; P heterogeneity: 0.69) in cohort studies.

Conclusion: Cohort studies consistently found a protective effect of total dairy products and milk intake, but the evidence is not supported by case–control studies. No relationship was found with cheese or yoghurt intake. As the number of cohort studies is still limited, their results need to be confirmed by other prospective studies.

Introduction

Milk and other dairy products are important components of human diet. They contribute about 4% of total energy worldwide and in some geographical regions, such as North America, Australia and Europe, milk and other dairy products provide about 10% of total energy intake (data extracted from Food Balance Sheets, FAO Statistical databases, 1995–1999, http://apps.fao.org). Cow's milk is the most frequently consumed, although there is considerable geographical variation with goat, sheep, camel and water buffalo milk.

Milk and dairy products have the peculiarity of having components that could hypothetically increase the risk of some diseases and other components that could decrease it. Milk has been suggested as a risk factor of atherosclerosis and coronary heart disease because it is a source of cholesterol and saturated fatty acids. Beneficial effects, however, have been attributed to other components of milk, like conjugated linoleic acid, which may have hypolipidaemic and antioxidative and thus antiatherosclerotic properties, calcium, which may protect from hypertension, and folic acid, vitamin B6 (pyridoxine) and B12 (cyanocobalamin), which contribute to lower homocysteine levels.

Laboratory and epidemiological studies suggest that the intake of dairy products could be associated with cancer risk (World Cancer Research Fund, 1997). Several studies have suggested that dairy consumption may be related to colorectal cancer risk. The main hypothesis underlying a possible protective effect of dairy products relates to their calcium content and to a lesser extent vitamin D, conjugated linoleic acid, sphingolipids, butyric acid and fermentation products. On the other hand, milk fats and particularly saturated fats might increase cancer risk.

The purpose of this review is to provide an overview of the principal hypotheses and epidemiological evidence of the possible links between milk and dairy products intake, and colorectal cancer. The first section outlines the main biological hypotheses about the possible association of dairy products and colorectal cancer risk. The second section is a summary of the published epidemiological studies. The results on milk, cheese and yoghurt are summarized using a meta-analytical approach. The results of studies on calcium and vitamin D are briefly described as they have been the object of other reviews recently published (Bergsma-Kadijk et al, 1996; Martinez & Willett, 1998).

Principal hypotheses linking dairy products intake and colorectal cancer

Calcium

Among various micronutrients, calcium has attracted significant interest as a potential chemopreventive agent. It has been proposed that ionized calcium (Newmark et al, 1984) or calcium phosphate (van der Meer et al, 1991) might reduce colon cancer by binding secondary bile acids and free fatty acids, primarily deoxycholic and lithocolic acids, thereby reducing their effective toxic dose to the colonic epithelial cells and preventing their stimulatory effects on proliferation of the intestinal mucosa (Lapre et al, 1993; Govers et al, 1996). Calcium has been shown to reduce the colonic content of diacylglycerol formed by bacteria which may activate cellular transduction pathways and has been postulated to increase proliferation in the colonic epithelium (Holt et al, 1996).

Another hypothesis derived from studies on human epithelial cells in vitro (Lipkin & Newmark, 1985; Lipkin, 1991) invokes an intracellular action of calcium, which could inhibit the proliferation of epithelial cells of the colon by inducing their differentiation (Lipkin & Newmark, 1995). It has been shown that administration of calcium to rodents reduces the incidence and multiplicity of chemically induced tumours (Appleton et al, 1987; Sitrin et al, 1991). Calcium also reduces the number of guanine-to-adenine mutations in the K-ras gene in colorectal neoplasms of the rat (Llor et al, 1991). Calcium may increase the rate of apoptosis occurring in colonic epithelial cells which, itself, could normalize a possible discrepancy between the proliferation/apoptosis ratio in preneoplastic mucosa (Chang et al, 1997).

Vitamin D

The foods naturally richest in vitamin D are fatty fish and fish oil. In most Western populations, however, intake of fatty fish and fish oil is low. Multivitamin supplements and enriched foods, particularly dairy products, can constitute a significant source of vitamin D (Chen et al, 1993; Holick, 1994).

Many tissues contain vitamin D receptors, including the colon. More differentiated colon cancer cells show higher levels of vitamin D receptors than less differentiated cell lines (Shabahang et al, 1993).

In 1980, Garland and collaborators proposed that vitamin D is protective against colon cancer. This hypothesis was based upon the geographical distribution of colon cancer deaths in the United States. In a subsequent study, Garland and coworkers found a significant reduction of the risk of developing colon cancer in subjects with higher levels of serum 25-hydroxyvitamin D (Garland et al, 1989).

Experimental studies suggest that vitamin D may inhibit cell proliferation (Shabahang et al, 1994; Cross et al, 1992; Wallach et al, 1966; Taniyama et al, 2000). The cell growth inhibitory properties of the vitamin appear to be related to the concentrations of vitamin D receptors on the cell surface rather than vitamin D concentrations. The inhibition might also be due to the effect of vitamin D on calcium absorption.

Fats

Dairy products could act as a dietary source of total and saturated fats. The major part (97–98%) of milk lipids is triglycerides or esters of fatty acids. The remainder comprises phospholipids (0.22–1%), sterols, free fatty acids and variable quantities of liposoluble vitamins (A, D, E and K). Around two-thirds of the fatty acids in milk are saturated. Polyunsaturated fatty acids make up less than 4% of milk fat.

The main hypothesis supporting a possible effect of fat on colon cancer risk is based on the intraluminal effect of products of fat digestion. It has been postulated that dietary fat may promote colon cancer by increasing bile acid and fatty acid excretion in the colonic lumen. The microbial flora hydrolyses bile acids to form secondary bile acids. Free fatty acids and ionized secondary bile acids may damage colonic epithelial cells and thus induce a compensatory hyperproliferation of crypt cells (van der Meer et al, 1991).

A more recent hypothesis is based on the circulatory effects of fat on increasing insulin concentrations. Evidence from animal studies suggested that insulin is an important growth factor of colonic epithelial cells and a mitogen of tumour cell growth in vitro (McKeown-Eyssen, 1994; Giovannucci, 1995). Some epidemiological studies have provided support for the theory that chronic hyperinsulinaemia consequent to insulin resistance increases colon cancer risk (Bird et al, 1996; Hu et al, 1999; Kaaks et al, 2000; Kono et al, 1998; Schoen et al, 1999; Will et al, 1998; Yamada et al, 1998).

Epidemiologic studies do not generally support the hypothesis that the total fat content of the diet increases colon cancer risk. However, it is possible that some subtype of fat could be related to colorectal carcinogenesis (Giovannucci & Goldin 1997).

Besides the postulated ‘negative’ effect of fat, other lipidic components of dairy products could be beneficial, such as butyric acid and conjugated linoleic acid (CLA). Butyric acid may inhibit proliferation and induce differentiation in a wide range of tumour cell lines in vitro (McBain et al, 1997; Parodi, 1999; Velazquez et al, 1996). Dietary butyric acid occurs exclusively in the lipid fraction of milk and its derivatives. Butyrate can likewise result from fermentation of dietary fibre by the microflora of the colon that has not been digested by intestinal enzymes. Some experimental studies have indicated a protective effect of butyric acid against colon cancer (Hague & Paraskeva, 1995; Hague et al, 1995; Aukema et al, 1997; Marchetti et al, 1997). Dietary butyric acids are rapidly absorbed by the intestine and are largely metabolized in the liver, and thus never reach the colon (Parodi, 1997). Consequently, it is unlikely that butyric acid from milk is involved in colon carcinogenesis in any way similar to that of butyrate produced by the colonic microflora from fibre fermentation.

Milk lipids constitute the principal dietary source of dietary CLA (Lin et al, 1995). Studies of cell lines have shown that CLA inhibits the proliferation of colorectal, breast and skin tumour cells (Parodi, 1997), mammary tumorigenesis in rats (Ip & Scimeca, 1997) and decreases the number of aberrant crypt foci in rats on 2-amino-3-methylimidazo [4,5-f] quinoline-induced colon carcinogenesis (Liew et al, 1995). CLA could have a cancer-protective effect by modifying the fluidity of cell membranes, reducing the synthesis of prostaglandins and/or stimulating the immune response (Parodi, 1997). Ip et al (1994) calculated that the anticancer properties of CLA in a rat mammary model of breast cancer are expressed at concentrations close to human consumption levels (0.1–1%). However, there is no consistent evidence of the postulated beneficial effects of these milk components in humans.

Lactic acid bacteria

The possible protective role on health of fermented dairy products such as yoghurt was originally proposed at the beginning of the last century. Metchnikoff in 1908 postulated that Lactobacillus bulgaricus, one of the various microbial species (Lactobacillus bulgaricus, Streptococcus thermophilus, Lactobacillus acidophilus, Bifidobacterium bifidus, etc.) that can be used in the preparation of fermented products, suppresses toxins produced by putrefactive bacteria in human intestines (cited by Meydani & Ha, 2000). Some strains of Bifidobacteria and Lactobacilli are known to bind the apical surface of colonic epithelial cells in culture without injuring them, which could explain their protective action in gastrointestinal diseases (Ouwehand et al, 1999). By protecting the surface epithelium, Bifidobacteria may thus facilitate repair and reduce irritation and epithelial permeability to electrolytes (Bruce et al, 2000).

Skim milk fermented with Bifidobacterium sp. may act against the development of aberrant crypt foci (ACF) in the colon of rats (Abdelali et al, 1995; Kulkarni & Reddy, 1994). Studies in vitro have shown that lactic acid bacteria have a capacity to absorb mutagens from cooked foods (Zhang & Ohta, 1993). This finding is consistent with an experimental study in humans in which it was observed that ingestion of L. acidophilus significantly reduced the excretion of mutagens following consumption of meat heavily browned or burnt by cooking at high-temperature (Lidbeck et al, 1992).

It has been suggested that yoghurt and other fermented products may have immunostimulatory properties related to their bacterial components. Oral administration to mice of milk containing L. bulgaricus or L. casei has been shown to activate the lymphocytes and macrophages (Perdigon et al, 1999). Addition of yoghurt to cultures of human blood lymphocytes stimulated by a mutagen leads to increased production of gamma-interferon, a cytokine with anti-proliferative properties that is able to activate natural killer (NK) cells (De Simone et al, 1987). The mechanism of intestinal colonisation by lactic acid bacteria has not yet been established, and it is likely that their consumption would have to be very frequent in order to have a significant effect on the intestine.

Hypotheses related to other milk components: proteins, folate, growth factors

Lactoferrin, a glycoprotein that participates in the transport and storage of iron, has a bacteriostatic effect by binding the iron that is necessary for microbial development. Lactoferrin may have other protective functions, by activating NK cells and stimulating lymphokine-activated killer (LAK) cells (Shau et al, 1992; Sekine et al, 1997). Human lactoferrin may inhibit the development of solid tumours of the colon and of metastases from a melanoma cell line in mice (Bezault et al, 1994; Yoo et al, 1997) and may reduce significantly the incidence and number of adenocarcinomas of the large intestine in rats (Sekine et al, 1997). The protective activity of lactoferrin against chemically induced rat tumours is consistent with results obtained using preparations of proteins from whey and other dairy products (Abdelali et al, 1995). Thus, even if lactoferrin should be confirmed to be a milk component with cancer–chemopreventive properties, the effect of lactoferrin would probably be limited for most dairy products because of its low natural concentration (0.02% in cows' milk) and its destruction by heat treatments used for milk conservation (Sekine et al, 1997). The lack of clinical and epidemiological data in humans precludes any firm conclusion on a specific effect of milk proteins in carcinogenesis.

There is some evidence that folate is associated with a reduced risk of colorectal neoplasia. Folates represent an important B vitamin, participating in one-carbon transfer reactions required in many metabolic pathways, especially purine and pyrimidine biosynthesis (DNA and RNA) and amino acid interconversions. One of the postulated mechanisms is that folate, central to methyl-group metabolism, may influence both methylation of DNA and the available nucleotide pool for DNA replication and repair (Freudenheim et al, 1991; Giovannucci et al, 1993).

Folate concentrations in cow's milk are in the range of 5–10 µg per 100 g. Fermented milk contains slightly higher amounts of folate, sometimes double, depending on the starter culture used. Most cheese varieties contain between 10 and 40 µg of folate per 100 g. Ripened soft cheese may contain up to 100 µg per 100 g (Forssen et al, 2000). The bioavailability of milk folates has not been fully determined under conditions of actual consumption, including the consequences of interactions between various food constituents. There is no evidence of the effect of milk folates on colorectal cancer risk.

Insulin-like growth factors (IFGs), IGF-I and IGF-II, present in mammalian milk, play an important role during gastrointestinal tract development. In vitro studies and animal experiments have shown that plasma IGF-1 may have direct effects on colorectal carcinogenesis, by stimulating cell proliferation, and by inhibiting apoptosis (Singh & Rubin, 1993). Research on growth-factor digestion in human adults is very limited, but it has been shown in animal experiments that IGF-II is stable in the gastro-intestinal tract in adult rats while IGF-I is less stable in the intestine of adult than in suckling rats (Philipps et al, 2000).

Epidemiological evidence on the association between dairy products and colorectal cancer risk

Most of the evidence in nutritional epidemiology comes from observational studies, such as case–control and cohort studies. Randomized controlled trials are less frequent, firstly because they are only justified when there is enough evidence of a possible benefit, and secondly because of the difficulties in randomizing subjects to different diets. Some intervention studies of calcium supplementation have been reported, but there are no trials on milk and/or dairy products and colorectal cancer.

At least 30 case–control or cohort studies have investigated the relationship between colorectal cancer and dairy products (Tables 1 and 2). The evidence for the four types of dairy products that were most often investigated (total dairy products, milk, cheese and yoghurt) is summarized in a meta-analysis. The measure of effect used is the weighted average relative risk/odds ratio (OR) of the highest category of consumption vs the lowest, as reported in the studies. The inverse of the variance of the ORs was used as weight and 95% confidence intervals (95% CI) were computed. Tests of heterogeneity were performed and random effect models used when there was evidence of heterogeneity (DerSimonian & Laird, 1986).

Table 1 Dairy products and colorectal cancer: case–control studies
Table 2 Dairy products and colorectal cancer: cohort studies

Total dairy products

Some studies evaluated the intake of all types of dairy products as a food group. The ORs for the highest category of consumption vs the lowest are summarized in Figure 1. Out of 11 case–control studies, three found a significant risk increase (Benito et al, 1990; Iscovich et al, 1992; Steinmetz & Potter, 1993) and three other studies a significantly decreased risk (Shannon et al, 1996; Kampman et al, 2000; Murata et al, 1999). The diversity of dairy products may to some extent explain the inconsistencies of these results. Case–control studies have heterogeneous results (P heterogeneity <0.0000) and, on average, do not provide evidence of association between total intake of dairy products and colorectal cancer risk (OR: 1.07; 95% CI: 0.84–1.34). One cohort study in male smokers in Finland (Pietinen et al, 1999) found a significant protective effect, while three cohort studies (Bostick et al, 1994; Kato et al, 1997; Hsing et al, 1998) found no significant protective association. The average result from cohort studies supports the hypothesis of a protective effect (OR: 0.62; 95% CI: 0.52–0.74). The assumption of homogeneity is not rejected (P heterogeneity: 0.93) for cohort studies, in contrast to what was found for case-control studies.

Figure 1
figure1

Odds ratios of colorectal cancer for ‘high’ vs ‘low’ dairy product consumption in case–control and cohort studies.

Milk

Two case–control studies found a significant risk increase associated to milk consumption. In one of them, conducted in Belgium, the risk increase was associated with milk consumption higher than 1775 g per week (Tuyns et al, 1988). The other study, conducted in the USA, evaluated the risk of different cancers in relation to milk consumption. This study found a significantly increased risk in subjects that consumed whole milk daily compared to non-consumers (Mettlin et al, 1990). The daily consumption of 2% fat-milk or skim milk was not associated with colon cancer but 2% fat-milk was found to be significantly protective for rectal cancer. Four case-control studies reported significant protective effects (Kune et al, 1987; Macquart-Moulin et al, 1986; La Vecchia et al, 1988), but not consistently for both sexes or both colon and rectum. The average estimate from case–control studies is OR: 0.98 (95% CI: 0.82–1.05; (Figure 2). As for dairy products, case–control studies were heterogeneous (P heterogeneity<0.00).

Figure 2
figure2

Odds ratios of colorectal cancer for ‘high’ vs ‘low’ for milk consumption in case–control and cohort studies.

The prospective studies published to date found reduced relative risks of colorectal cancer associated with higher levels of milk consumption. The cohort from Finland in male smokers (Pietinen et al, 1999) and the prospective study on an Adventist population (Singh & Fraser, 1998) found a significant protection. Only the Adventist study found a non-significant relative risk higher than 1 in women (Phillips & Snowdon, 1985). On average, cohort studies are supportive of a protective effect of milk consumption (OR: 0.80; 95% CI: 0.68–0.95; P heterogeneity: 0.77).

Cheese

No association between cheese consumption and colorectal cancer risk was found on average by case-control and cohort studies (Figure 3). The average estimate for case–control studies is OR 1.07 (95% CI: 0.87–1.32; P heterogeneity: 0.02) and OR 1.10 (95% CI: 0.88–1.36) for cohort studies. Homogeneity is not rejected for cohort studies (P heterogeneity: 0.55).

Figure 3
figure3

Odds ratios of colorectal cancer for ‘high’ vs ‘low’ cheese consumption in case–control and cohort studies.

Yoghurt

The number of studies that have investigated the effect of yoghurt intake in colorectal cancer is limited (Figure 4). So far, case–control and cohort studies are not supportive of the hypothesis of a protective effect. Homogeneity is not rejected for case-control studies (P heterogeneity: 0.69), nor for cohort studies (P: 0.69). The average estimates are OR 0.93 (95% CI: 0.84–1.03) for case–control and OR 1.03 (95% CI: 0.83–1.28) for cohort studies.

Figure 4
figure4

Odds ratios of colorectal cancer for ‘high’ vs ‘low’ yoghurt consumption in case-control and cohort studies.

Fat from milk and dairy products

Some epidemiological studies have investigated low-fat dairy products separately from high-fat dairy products. One case-control study (Miller et al, 1983) did not find significant associations between low-fat and high-fat dairy products and colorectal cancer risk with the exception of a significant risk increase in rectal cancer in women associated with an intake higher than 16 g per day of cream, milk desserts, ice cream, ice milk and sherbert cheese. Two other case–control studies (Iscovich et al, 1992; Shannon et al, 1996) reported higher odds ratios for high-fat than for low-fat dairy intake, but the association was not statistically significant. An American hospital-based case–control study on patterns of milk consumption and risk of different cancers found a significant increased risk in subjects that consumed whole milk daily compared to non-consumers (Mettlin et al, 1990). In this study, the daily consumption of 2% milk or skim milk was not associated with colorectal cancer. The data were not adjusted for total caloric intake. A prospective study on an Adventist population (Singh & Fraser, 1998) found a relative risk of 1.04 (95% CI: 0.69–1.59) for consumption of whole milk more often than once a week compared with no consumption. The relative risk for the same levels of consumption of non-fat milk was 0.78 (95% CI: 0.48–1.28). These results are suggestive of a risk increase associated with intake of high-fat dairy products. Nevertheless, these results could hardly be interpreted as an evidence of the fat hypothesis, first because of the sparse number of studies and secondly, because no association was found when investigating other dairy products richer in fat, such as cheese.

Calcium

A recent meta-analysis (Bergsma-Kadijk et al, 1996) and a review of the epidemiological evidence from published case–control and cohort studies (Martinez & Willett, 1998) concluded that calcium intake was not associated with a substantially lower risk of colorectal cancer or polyps. Studies published after these two reviews support the hypothesis that high levels of calcium may reduce the risk of colorectal cancer. A cohort study in Finland observed a significant 40% reduction in risk of colon cancer at high levels of calcium intake (Pietinen et al, 1999) as did a large multi-centre case–control study from the USA (Kampman et al, 2000) and a case–control study conducted in Wisconsin (Marcus & Newcomb, 1998). A prospective study among Iowa women also suggested an inverse association between calcium and colon cancer, but limited to the subjects without a history of colorectal cancer among first-degree relatives (Sellers et al, 1998).

Two major different end points have been used in clinical trials as intermediate biomarkers of risk of colorectal neoplasia: the recurrence of adenomatous polyps, a last intermediate biomarker of risk, and colorectal epithelial cell proliferation, an earlier biomarker. The results of five small uncontrolled clinical trials (Lipkin & Newmark, 1985; Buset et al, 1986; Lipkin et al, 1989; Rozen et al, 1989; O'Sullivan et al, 1993), nine small randomized placebo-controlled trials (Gregoire et al, 1989; Stern et al, 1990; Barsoum et al, 1992; Wargovich et al, 1992; Thomas et al, 1993; Bostick et al, 1993; Cats et al, 1995; Weisgerber et al, 1996; Bostick et al, 1997) and three full-scale randomized placebo-controlled trials (Armitage et al, 1995; Baron et al, 1995; Bostick et al, 1995) suggested that it is unlikely that calcium supplementation can substantially lower colorectal epithelial cell proliferation rates, but it may normalize the distribution of proliferating cells within colon crypts, as reviewed by Bostick, (1997). This is still consistent with the hypothesis that a higher consumption of calcium may reduce the risk of colorectal cancer.

More recent studies have not provided on average evidence of a beneficial effect of calcium supplementation on epithelial cell proliferation. In a double-blind, placebo-controlled randomized trial involving supplementation of fibre and calcium intake in 93 patients with resected colorectal adenomas, neither the wheat bran fibre nor the calcium carbonate supplements significantly reduced cellular proliferation rates in rectal mucosal biopsies (Alberts et al, 1997). A randomized trial of calcium and antioxidant vitamins on 77 patients operated on for colorectal cancer showed that calcium and vitamin supplementation does not reduce cell kinetics of the colon (Cascinu et al, 2000). Only a small, 1 y trial of calcium supplementation found a significant suppression of rectal epithelial cell proliferation levels in the intervention group (Rozen et al, 2001).

Recent trials on recurrent adenomas are suggestive of a beneficial effect of calcium supplementation, though modest. A double-blind 3 y intervention with calcium and antioxidants in 116 polyp-bearing patients showed a beneficial effect on adenoma recurrence, although not on adenoma growth (Hofstad et al, 1998). The Calcium Polyp Prevention Study, a large clinical controlled trial, showed that calcium carbonate supplementation was associated with a significant, though moderate, reduction in the risk of recurrent adenomas (Baron et al, 1999). In the European Cancer Prevention Intervention Study, a placebo-controlled trial on the prevention of adenoma recurrence in 655 patients, calcium supplementation was associated with a modest but not significant reduction in the risk of adenoma recurrence (Bonithon-Kopp et al, 2000).

Vitamin D

Whereas the relation between calcium and colon or colorectal cancer has been studied in numerous epidemiological studies, the role of vitamin D has only been addressed in a smaller number of epidemiological studies. The available results for vitamin D suggest protective rather than harmful effects of vitamin D on colon cancer risk, as reviewed by Martinez and Willett (1998). Only one of the three case–control studies identified in the review reported a significant protective effect of dietary vitamin D against colorectal cancer risk. Three other studies not included in the review reported discordant results: a French case–control study (Boutron et al, 1996) that did not find association between vitamin D intake (nor calcium) and colorectal cancer risk; a Swedish study (Pritchard et al, 1996) that reported a protective effect of dietary vitamin D, more pronounced for cancer of the rectum (no association with calcium); and a large case–control study (Kampman et al, 2000) that found an inverse significant association of dietary calcium and calcium supplement use with colon cancer, but no significant association with dietary vitamin D, supplements or sunshine exposure. Four of the five prospective studies included in the review have reported an inverse association for dietary vitamin D and colon cancer, but this was only significant in the Western Electric study (Garland et al, 1985). This was a small prospective study with only 49 colorectal cancer cases identified after 19 y of follow-up. The same author reported a protective effect of serum 25-hydroxyvitamin D on colon cancer from a nested case–control study, but only 34 cases of colon cancer were included (Garland et al, 1989).

The significant risk reduction among high vitamin D consumers has not been confirmed by any of the prospective studies. As most studies that observed an inverse association with vitamin D intake are prospective studies in which exposure is assessed many years before diagnosis, it is possible that vitamin D has a protective effect only on early stages of tumour development (Kampman et al, 2000).

One of the hypotheses currently under discussion relating cancer and vitamin D is its potentially protective effect against prostate cancer (Miller et al, 1995; Giovannucci, 1998). This hypothesis is based on the possible role of vitamin D as a moderator of cell proliferation and differentiation, and on a range of epidemiological, clinical and biological observations on risk factors traditionally associated with prostate cancer (black race, geographic origin in terms of a north/south gradient, and advanced age), which have a common associated feature of a low level of endogenous 1, 25-(OH)2 vitamin D. Calcium could play an indirect role in the development of prostate cancer, through a reduction in plasma levels of the active form of vitamin D (1, 25-(OH)2 vitamin D), in contrast to the potentially protective effect of calcium against colon cancer that was discussed in the previous section.

Conclusions

The main conclusions which can be reached based on our review and meta-analysis are that there is some epidemiological evidence that the consumption of total dairy products and in particular milk, may be associated to a modest reduction in colorectal cancer risk. This evidence is limited to cohort studies, while case–control studies provided heterogeneous results. We found no evidence of either reduction or increase of colorectal cancer risk specifically associated with consumption of cheese or yoghurt.

However, our conclusions should be taken with caution. The reviewed epidemiological studies and the meta-analytical procedure used to obtain a summary estimate of the association have some limitations, such as the large variability in the type and composition of the dairy products consumed in different study populations, which for practical purposes were condensed in three or four food groups, the intrinsic methodological limitations of the dietary measurement obtained through usual questionnaires and, last but not least, publication bias, which may distort the representativeness of available results.

For future research, it will be essential to conduct further epidemiological studies on specific types of dairy products and to study the mechanisms of action of each of their components in experimental carcinogenesis models, as well as their possible interactions. The possibility of using specific biological markers of consumption of milk lipids, such as pentadecanoic (C15) and heptadecanoic (C17) acids (Wolk et al, 1998) opens some perspectives for clinical and epidemiological research into the specific roles of fatty acids from dairy products in carcinogenesis. The measurement of other biological markers such as plasma levels of 1,25-(OH)2 vitamin D and 25-(OH) vitamin D and calcium in human studies in addition to classical analyses of the main food groups may allow better estimation of individual exposures, and testing of hypotheses on the specific roles of milk and its components in cancer etiology, which until now have been developed mainly within the context of experimental studies.

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Correspondence to E Riboli.

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Norat, T., Riboli, E. Dairy products and colorectal cancer. A review of possible mechanisms and epidemiological evidence. Eur J Clin Nutr 57, 1–17 (2003). https://doi.org/10.1038/sj.ejcn.1601522

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Keywords

  • dairy products
  • milk
  • cheese
  • yoghurt
  • colorectal cancer
  • meta-analysis

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