Carcinogenesis

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Carcinogenesis, Vol. 20, No. 6, 927-931, June 1999
© 1999 Oxford University Press

Accelerated Paper

Effects of soy or rye supplementation of high-fat diets on colon tumour development in azoxymethane-treated rats

Margaret J. Davies, Elizabeth A. Bowey, Herman Adlercreutz¹, Ian R. Rowland² and Paul C. Rumsby³

BIBRA International, Woodmansterne Road, Carshalton, Surrey SM5 4DS, UK and
¹ Department of Clinical Chemistry, University of Helsinki and Folkhälsan Research Center, PO Box 60, FIN-00014, Helsinki, Finland

	Abstract

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Evidence is accumulating that a diet high in plant-derived foods may be protective against cancer. One class of plant component under increasing investigation is the phytoestrogens of which there are two main groups: the isoflavones, found mainly in soy products, and the lignans, which are more ubiquitous and are found in fruit, vegetables and cereals with high levels being found in flaxseed. In this study, we have used carefully balanced high-fat (40% energy) diets: a control diet (containing low isoflavone soy protein as the sole protein source), a rye diet (the control diet supplemented with rye bran) and a soy diet (containing as protein source a high isoflavone soy protein). The effect of these diets on the development of colonic cancer was studied in F-344 rats treated with the carcinogen, azoxymethane (two doses of 15 mg/kg given 1 week apart). Colons from treated animals were examined for aberrant crypt foci (ACF) and tumours after 12 and 31 weeks. Results after 12 weeks showed no differences in the total number of ACF in the control, soy or rye bran groups. However, the soy group had increased numbers of small ACF (less than four crypts/focus) while the rye group had decreased numbers of large ACF (greater than six crypts/focus). Examination of colons after 31 weeks gave similar low numbers of ACF in each group with no differences in multiplicity. There were no differences in the number of tumours between the control (1.36 tumours/rat) and soy (1.38 tumours/rat) groups. However, there was a significant decrease in the number of tumours in the rye group (0.17 tumours/rat). These results suggest that soy isoflavones have no effect on the frequency of colonic tumours in this model while rye bran supplementation decreases the frequency of colon cancer. This effect is due not to a decrease in early lesions but in their progression to larger multi-crypt ACF. The study also supports the hypothesis that larger ACF are more predictive of subsequent tumorigenicity.

Abbreviations: ACF; aberrant crypt foci; AOM; azoxymethane.

	Introduction

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The role of diet in the aetiology of certain cancers is well recognized and much attention has been focused on potential protective factors present in food. Plant-based diets and, in particular, whole grains, legumes, fruit and vegetables have been associated with a lower incidence of cancer, such as those of the breast and colon (1). Evidence for a link between grain fibre intake and cancer incidence is somewhat less conclusive, suggesting that other factors present may be responsible for the protective effects observed with whole grains (2).

Recently, there has been much interest in classes of phenolic compounds with oestrogen-like activity, phytoestrogens, and their potential protective effects against cancer. Phytoestrogens in general bind weakly to the oestrogen receptor and fail to exert a full oestrogenic response, and so may be antagonising oestrogens and exhibiting both oestrogenic and antioestrogenic effects (reviewed in ref. 3). These phytoestrogens fall into two main groups, isoflavones and lignans. Soy products are the main sources of isoflavones (up to 100 mg/100 g), whilst lignans are more widely distributed in grains (especially wheat and rye) and fruit and vegetables (0.1–1.0 mg/100 g); flax seeds provide the highest levels of lignans with up to 50 mg/100 g (4).

Phytoestrogens have been reported to be protective for hormonal cancers, such as those of the breast and prostate, and for colon cancer (reviewed in refs 4,5). Their anti-oestrogen properties are often considered to be responsible for the cancer-preventing effects. However, they also exhibit antioxidant activity and have been shown to influence cell proliferation, intracellular enzymes and protein synthesis (5–7).

In this study, we have examined the effects of the two phytoestrogen classes, soy isoflavones and rye bran lignans, in the azoxymethane (AOM)-induced rat colon cancer model. We have looked at the early precancerous lesions, aberrant crypt foci (ACF), 12 weeks after carcinogen treatment, and tumour incidence at 31 weeks, in order to provide information on the influence of phytoestrogens at different stages of carcinogenesis.

Studies of the biological effects of phytoestrogens are often confounded by the presence of other potential cancer-preventing substances in the foods containing phytoestrogens, notably dietary fibre and phytate in cereals and grains, and non-digestible oligosaccharide and protease inhibitors in soy. We have formulated the diets used in this study to provide the same levels of these substances in all groups.

	Materials and methods

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Diet
A diet has been devised by an EU-funded phenolic phytoprotectants group for use in a number of different animal studies (8,9). The diets were formulated to reflect some of the characteristics of the Western European diet considered to be important for a high risk of colon cancer, namely high fat (40% of total energy) and low calcium (10). This diet (the constituents of which are given in Table I) is based on soy protein with isoflavones removed (control group, 0.09 mg/g protein supplied), isoflavone-containing soy protein (soy group, 2.46 mg/g protein) and low isoflavone soy protein with added 30% rye bran (rye group). The use of soy protein with the isoflavones extracted, in the basic control diet enabled us to avoid the problem of differences in protein source which may influence tumour incidence (11). A cellulose-based fibre (Solka Flok) was added to the diet for the control and soy groups. Fibre was provided by the rye bran in the rye group.

View this table: [in this window] [in a new window]   Table I. Diets used in the study

 
Experiment design
The design of the study is outlined in Table II. Six-week-old male Fischer-344 rats were fed the experimental diets for 1 week, then received an s.c. injection of the colon carcinogen, AOM (15 mg/kg) or saline (controls), followed by a second injection 1 week later. Twelve weeks after the first injection six animals from each group were killed, their colons removed and examined for ACF as outlined below. The remaining animals were killed after 31 weeks and the colons removed and analysed for both ACF and tumours. Body weights and food intakes were measured at intervals of 4 weeks during the study.

View this table: [in this window] [in a new window]   Table II. Design of study

 
Analysis of ACF and tumours
The ACF were detected as described previously (12). The colons were slit longitudinally, mounted flat on card and fixed in 70% ethanol. The mucosal surface was stained with 0.1% methylene blue and excess stain removed with phosphate-buffered saline and examined under a stereomicroscope. The ACF were identified as darker staining regions among the normal crypts of the mucosal layers, showing at least one of the following characteristics: increased size, thicker epithelial lining, distortion of the lumina and increased pericryptal zone (13). The number of aberrant crypts in each focus was recorded, together with its location (in cm) from the anal end of the colon, 1 cm above the anus. The number of tumours and their position in the colon were recorded.

Statistical analysis
Statistical analysis was carried out using ANOVA and Student's t-test.

	Results

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No ACF or tumours were seen in rats that were not treated with AOM. As expected, AOM treatment induced large numbers of ACF in all groups of animals (Figure 1; Table III). Both the soy- and rye-fed rats given AOM exhibited more ACF/colon at 12 weeks than the control animals, although this was significant only for small ACF, in particular ACF with a single aberrant crypt (Figure 1). The number of large ACF (greater than four crypts/focus) was lower in the rye-fed animals and higher in the soy-fed rats than in the controls, although the results only reached significance with foci containing eight crypts (Table III; Figure 1) and when the total number of foci of six crypts and above were analysed. Previous studies show that these larger foci seem to correlate more closely with subsequent development of colon cancer (12,14,15).

View larger version (25K): [in this window] [in a new window]   Fig. 1. Analysis of ACF the colon at 12 weeks. Control mean, soy mean, rye mean—the mean number of aberrant crypts per focus in each group. Control total, soy total, rye total—the total number of ACF per colon in each group. Asterisks show values significantly different from those of the control group: *P < 0.05; **P < 0.01. All other values are not significantly different from those of the control group.

 

View this table: [in this window] [in a new window]   Table III. Analysis of ACF after 12 weeks

 
The total number of ACF observed decreased considerably from week 12 to week 31 (25- to 60-fold decrease; Tables III and IV). Many of these ACF appear to be transient lesions which are either removed or remodelled to normal colonic crypts (12). No significant differences were observed in the total numbers of ACF between the dietary groups at 31 weeks, or in the multiplicity of the crypts (Table IV). In all cases, the ACF were located in the distal colon, whereas some tumours were found in the proximal colon (Figure 2).

View this table: [in this window] [in a new window]   Table IV. Analysis of ACF and tumours at 31 weeks

 

View larger version (9K): [in this window] [in a new window]   Fig. 2. Position of colonic tumours at 31 weeks. •, Position of individual colonic tumours in each treatment group measured from the anal end of the colon.

 
Table IV shows the number of tumours and ACF found in the colon at 31 weeks. This clearly shows that the rye diet lowered the number of colon tumours while the soy diet had no effect when compared with animals on the isoflavone-free, control diet. The size and location (Figure 2) of tumours were similar for the control and soy diets. The small number of tumours seen with rye made comparison impossible for this group.

No ACF or tumours were seen in any of the control animals not treated with AOM.

	Discussion

Top Abstract Introduction Materials and methods Results Discussion References

 
The results of this study lead us to conclude that soy isoflavones have no protective effects on carcinogenesis in the colon of AOM-treated rats either on the basis of ACF or colonic tumours. In fact there was an increase in the number of smaller ACF observed at 12 weeks. Previous animal studies on phytoestrogens from soy have proved somewhat inconsistent. A recent study by Rao et al. (16) showed an increase in tumours (mainly non-invasive) in AOM-treated rats fed the pure isoflavone, genistein, while earlier studies found genistein to inhibit AOM-induced ACF after 5 weeks of feeding (17,18). The study reported here shows that the relationship between ACF formation and the development of tumours may be complex.

While there is some epidemiological evidence for protective effects of soy products on colon cancer, a number of studies have shown no effect (reviewed in refs 4,5). A further possibility is that soy is consumed mainly in populations with Eastern-style diets and perhaps soy does not protect against high-fat Western diets. It is important to remember, however, that soy products contain many other putative protective factors in addition to phytoestrogens, e.g. oligosaccharides and protease inhibitors, which may be responsible for the cancer preventing effects at some sites (19).

Recent studies with the min mouse, which contains a mutation in the adenomatous polyposis coli (APC) locus and a further one in the mom-1 gene, showed no effects with added soy flour (8; P.C.Rumsby and M.J.Davies, unpublished observations). The min mouse model with constitutive mutations in both APC and mom-1 and an endpoint of adenomas in the small intestine may actually be measuring different events than the AOM-induced colon tumour model. For instance, it may not be a good model when there is interaction with the gut microflora, which takes place mainly in the colon. Also, the mutation may mean that the model is too far established in the development of tumours for diet to be effective (20). It is noteworthy that a recent study feeding a vegetable/fruit mixture gave increased numbers of polyps (9) suggesting that the min mouse may have limitations for studies on diet and cancer.

In vitro studies on soy products have shown an anti-proliferative effect on a wide range of cell types including those derived from the human gastrointestinal tract (7). The isoflavones have also been shown to have antioxidant and anti-promotional effects and to be associated with the inhibition of tyrosine protein kinases, DNA topoisomerases and phosphatidylinositol breakdown in various in vitro systems (reviewed in ref. 5).

The rye-bran-treated group showed a marked highly significant decrease in the number of colon tumours. Analysis at 12 weeks showed no change in the total number of ACF, but there was a small decrease in the number of large ACF (greater than six crypts/focus). These larger ACF have been shown to predict more accurately preneoplastic potential (12,14,15).This suggests that the rye bran may act by retarding progression of the early aberrant crypts although further work is required to elucidate this possible protective mechanism of rye bran. These data do, however, add to the evidence that multiplicity of crypts in ACF is a more accurate predictor of subsequent tumour formation than simple total numbers of ACF.

Because we balanced the control and rye diets with respect to other putative cancer-preventing components such as fibre and phytate, it appears likely that the lignans in the rye are responsible for at least part of this effect. It is unlikely that differences in the properties of the fibre source (rye bran versus cellulose) accounted for the effect of the rye bran in the diet. One possible protective effect of fibre is the increased absorption of carcinogens by the fibre. However, AOM is a hydrophilic carcinogen and is poorly adsorbed by fibre. Also, the protective effect observed here does not appear to be on the prevention of initiation of primary lesions where the mutagenic action of AOM might be expected to have an effect. Other studies on AOM-induced colon cancer which suggest a protective action for fibre, e.g. wheat bran (21–23), have used a low fibre versus high fibre regimen. This study has used equivalent amounts of fibre in the control diet as in the rye bran diet. Therefore, it seems most likely that the protective effect is due to the presence of lignans in the rye bran diet.

Jenab and Thompson (24) have reported that feeding AOM-treated rats flaxseed, which has a much higher concentration of lignans than rye, decreased the number of ACF as did a daily gavage of 1.5 mg of the pure lignan, secoisolariciresinol (seco). Flaxseed was also protective against mammary tumours. High levels in the urine of enterolactone produced by bacterial breakdown of seco in the mammalian gut, like equol, a similar product of isoflavones, are associated with a reduced risk of breast cancer (25,26). However, the difference between isoflavones and lignans in protecting against colon cancer suggests that they may have a different non-hormonal mechanism of action. There is some evidence that lignans may protect against colon cancer in humans.

In conclusion, soy isoflavones did not protect against the development of colon tumours in AOM-treated rats fed a high fat, high risk diet. In contrast, the rats fed the rye bran diet had significantly less tumours, thus providing support for the limited evidence in humans for a protective effect for rye lignans (4).

	Acknowledgments

 
We would like to thank Joanne Turner, James Coutts, Cathy Smith and Davina Smith for technical assistance. This study was funded by the European Union FAIR Programme (contract no. CT95-0894) and the World Cancer Research Fund.

	Notes

 
² Present address: Northern Ireland Centre for Diet and Health, School of Biomedical Sciences, University of Ulster, Coleraine BT52 1SA, UK

³ To whom correspondence should be addressed Email: prumsby{at}bibra.co.uk

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Received February 5, 1999; revised March 8, 1999; accepted March 12, 1999.

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