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© 2007 American Society for Nutrition J. Nutr. 137:2285-2290, October 2007

Nutrition and Disease

Three Nordic Berries Inhibit Intestinal Tumorigenesis in Multiple Intestinal Neoplasia/+ Mice by Modulating ß-Catenin Signaling in the Tumor and Transcription in the Mucosa1–3,

Marjo Misikangas4,6, Anne-Maria Pajari4,6, Essi Päivärinta4,6, Seija I. Oikarinen4, Johanna Rajakangas4, Maija Marttinen4, Heidi Tanayama4, Riitta Törrönen5 and Marja Mutanen4,*

4 Department of Applied Chemistry and Microbiology (Nutrition), University of Helsinki, FIN-00014 Helsinki, Finland; and 5 Food and Health Research Centre, Department of Clinical Nutrition, University of Kuopio, FIN-70211 Kuopio, Finland

* To whom correspondence should be addressed. E-mail: marja.mutanen{at}helsinki.fi.


   ABSTRACT
TOP
 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 LITERATURE CITED
 
Berries contain a number of compounds that are proposed to have anticarcinogenic properties. We studied the effects and molecular mechanisms of wild berries with different phenolic profiles on intestinal tumorigenesis in multiple intestinal neoplasia/+ mice. The mice were fed a high-fat AIN93-G diet (Con) or AIN93-G diets containing 10% (w:w) freeze-dried bilberry, lingonberry (LB), or cloudberry (CB) for 10 wk. All 3 berries significantly inhibited the formation of intestinal adenomas as indicated by a 15–30% reduction in tumor number (P < 0.05). CB and LB also reduced tumor burden by over 60% (P < 0.05). Compared to Con, CB and LB resulted in a larger (P < 0.05) proportion of small adenomas (43, 69, and 64%, respectively) and a smaller proportion of large adenomas (56, 29, and 33%, respectively). ß-Catenin and cyclin D1 in the small and large adenomas and in the normal-appearing mucosa were measured by Western blotting and immunohistochemistry. CB resulted in decreased levels of nuclear ß-catenin and cyclin D1 and LB in the level of cyclin D1 in the large adenomas (P < 0.05). Early changes in gene expression in the normal-appearing mucosa were analyzed by Affymetrix microarrays, which revealed changes in genes implicated in colon carcinogenesis, including the decreased expression of the adenosine deaminase, ecto-5'-nucleotidase, and prostaglandin E2 receptor subtype EP4. Our results indicate that berries are potentially a rich source of chemopreventive components.


   Introduction
TOP
 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 LITERATURE CITED
 
Colorectal cancer is among the major cancers and one of the leading causes of cancer-related deaths in Western societies. Its occurrence is strongly affected by environmental factors such as diet, which enables prevention and treatment with dietary and pharmacological compounds, and promising plant-derived cancer preventive agents have been studied (1). These compounds could provide successful cancer prevention without the undesirable side-effects seen with many drugs (2,3).

The most promising anticarcinogenic agents in plants are phenolic compounds, which are abundant in berries (1). Concomitantly, berries and their extracts have been shown to be chemopreventive at several stages of the carcinogenic process (4). In the Nordic countries, wild berries are easily available and commonly consumed. In Finland, the incidence of colorectal cancer differs up to 2-fold between the North and the South (5), which is accompanied by a higher consumption of wild berries in the North. To study the possible chemopreventive properties of wild berries and their effects on spontaneous intestinal tumor formation in the Min/+ mouse, we studied 3 berries with different phenolic profiles (6,7): bilberry [(BB),7 Vaccinium myrtillus], lingonberry (LB, Vaccinium vitis-idaea), and cloudberry (CB, Rubus chamaemorus), which are rich in anthocyanins, proanthocyanidins, and ellagic acid, respectively.

Min/+ mice have a heterozygous, dominant mutation in the adenomatous polyposis coli (Apc) gene, leading to improper regulation of cellular ß-catenin pools, which is the driving force in Apc-induced colonic neoplasia. In the early studies with APC-mutated colon carcinoma cells, it was shown that ß-catenin is in the nucleus as part of the T-cell factor/lymphoid enhancer factor (Tcf/Lef) transcription factor in constitutively transcriptionally active form and reintroducing wild-type APC efficiently removes ß-catenin from the Tcf/Lef complex (8). The cellular levels of ß-catenin are increased at all stages of colon carcinogenesis, including dysplastic aberrant crypt foci, adenomas, and invasive carcinomas in colon cancer patients (9–13), as well as in animal models of colon cancer (14,15). In the nucleus, Tcf/Lef-ß-catenin complex activates a wide variety of Wnt-responsive genes such as cyclin D1 (16), which is frequently overexpressed in colon cancer (17–19). Nuclear staining of cyclin D1 increases significantly from low-grade dysplastic adenomas to high-grade dysplasia (20) and it also correlates with early onset of cancer and risk of tumor progression and metastasis (17–19). A wide variety of anti-inflammatory substances exert their chemopreventive effects in colorectal cancer by inhibiting nuclear accumulation of ß-catenin and expression of cyclin D1 (21–23).

In this study, all 3 berries proved to be chemopreventive. To further study the mechanism of cancer prevention, we investigated the effects of berries on the Wnt-signaling pathway. ß-Catenin and cyclin D1 were measured in small and large adenomas separately to determine whether the berries could prevent accumulation of ß-catenin and cyclin D1 during adenoma growth. To elucidate early changes in cell signaling by the berries, we also carried out an Affymetrix microarray assay on the normal-appearing mucosa.


   Materials and Methods
TOP
 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 LITERATURE CITED
 
    Experimental design and diets. The Laboratory Animal Ethics Committee of the University of Helsinki, Finland approved the study protocol. Male and female C57BL/6J Min/+ mice were bred at the Experimental Animal Unit of the University of Helsinki from inbred mice originally obtained from Jackson Laboratory. Mice were genotyped by PCR assay for the Apc allele. At the age of 5 wk, 45 Min/+ mice were stratified by litter and sex and assigned randomly to the control or experimental diets, with 10–12 mice per group, each consisting of 5–6 male and 4–6 female mice. Mice were housed in plastic cages in a temperature- and humidity-controlled facility, with a 12-h-light/-dark cycle. The mice had free access to the semisynthetic diets and tap water for 10 wk. We recorded their body weights weekly.

The mice were fed modified high-fat AIN93-G diets (15,24) containing 10% (w:w) freeze-dried BB, LB, or CB. The berries were from the same batch obtained from Kiantama Oy (Suomussalmi, Finland). The control diet (Con) was a similar high-fat diet without any added berries. All diets provided 41% of their energy from fat, 39% from carbohydrates, and 19% from protein (Table 1). When eating the same amount of energy, the diets provided similar amounts of fat, carbohydrate, and protein, as well as other components of the diets, except for those provided by berries. The concentrations of anthocyanins, flavonols, and total ellagic acids in the diets were based on the values analyzed from the freeze-dried berries by the methods described earlier (6,7). The diets were prepared at the beginning of the feeding period, vacuum-packed in weekly portions, and stored at –20°C.


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  		TABLE 1 Composition of diets

 
After 10 wk of treatment, the mice were killed by CO2 inhalation and the small intestine, cecum, and colon were removed, opened along the longitudinal axis, and rinsed with ice-cold saline. The small intestine was divided into 5 equal segments. Distal small intestine represented 60% of the small intestine from the distal end. Two observers unaware of the dietary treatment counted the number and measured the diameter of all adenomas in each segment using a dissecting microscope at 67x magnification. The adenoma burden was calculated as a sum of the areas ({pi}r2) of all the adenomas for each mouse. Adenomas were categorized as small (diameter ≤ 1.0 mm) and large (diameter ≥ 1.1 mm), excised, and pooled according to the size category separately from each segment. The adenomas >0.3 mm were reliably detected and possible adenomas smaller than that were excluded from the analyses. During the procedure, the samples were kept on ice. All samples were frozen in liquid N2 and stored at –70°C.

    Western blotting. Sample preparation and Western blotting has been described in more detail in our previous study (25). Briefly, adenomas from the 3 most distal segments of the small intestine were pooled according to the size category. Samples were further fractionated to nuclear, cytosolic, and membranous fractions for each mouse. We used the following primary antibodies: anti-ß-catenin (Sc-7199, Santa Cruz Biotechology) and anti-cyclin D1 (RM-9104, NeoMarkers). Equal loading of samples was ensured by incubating blots with actin antibody (A5441, Sigma-Aldrich). Results are shown as median values of band intensity (relative units).

    Immunohistochemistry. Tissue samples for immunohistochemistry were taken from the proximal part of the ileum and analyzed as described earlier (25). Staining for ß-catenin (Transduction Laboratories), E-cadherin (Transduction Laboratories), and cyclin D1 (NeoMarkers) was scored separately in the crypt and villus compartments. Distributions and relative staining intensities were determined with a scale ranging between 0 (no staining) and 5 (very strong staining) at 0.5-units intervals by 2 observers who were unaware of the dietary treatment. A scale for staining intensity of cyclin D1 ranged between 0 (no staining) and 3 (very strong staining).

    Affymetrix microarray. The mucosa samples for RNA extraction were taken from the ileum immediately after the tissue was confirmed to be free of any tumors. The samples were kept in RNA stabilization reagent (Qiagen) until isolation. Total RNA was extracted from the mucosa of each animal using the RNeasy Mini kit (Qiagen). Purity and integrity of the extracted RNA were verified by spectrophotometry and agarose gel electrophoresis. Equal amounts of total RNA from 10–12 mice of each diet group was used to prepare 3–4 pooled RNA samples (2–4 mice per pool) for each group for hybridization to a MG-U74Av2 array (Affymetrix). The labeling, hybridization, and scanning of the arrays were performed at the Centre for Biotechnology, University of Turku, Finland, according to Affymetrix guidelines.

    Statistical analysis. The results are expressed as the median (min-max) and tested by nonparametric methods (SPSS Inc., version 10.0) due to the small number of samples (n = 10–12 per group). Differences were considered significant at P < 0.05. Male and female mice were pooled in the analysis, because the only difference between them was the higher final body weight in male mice (27.0–29.2 g) than in the females (20.0–22.6 g) (P < 0.05). The body weights, adenoma data, Western blotting data, and immunohistochemical staining scores between the control and the berry groups were analyzed by Mann-Whitney U-test. The Spearman correlation was used to study the relation between adenoma and staining data and Wilcoxon's Signed Rank test to study the difference between the small and large adenomas and between the villus and crypt.

The Affymetrix data consist of expression profiles of 12,488 transcripts in MG U74Av2 array. The Affymetrix microarray suite 5.0 generated raw data in the form of ‘CEL’ files were imported into GeneSpring program (Agilent) and normalized by GC-Robust Multichip Average. Further statistical analyses were carried out using GeneSpring software. There were significant correlations between expression profiles of the biological replicates within the diet groups. The effects of dietary treatments on gene expression were evaluated by one-way ANOVA with a cut-off value of P < 0.05. The resulting gene list was used for testing each berry treatment against the control by filtering for 2-fold or more increase or decrease in gene expression based on all replicates in each group and by using Student's t test.


   Results
TOP
 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 LITERATURE CITED
 
    Formation of adenomas. The mice grew well throughout the experiment and no adverse effects of berries were observed.

All the berries significantly inhibited the formation of intestinal adenomas, as indicated by a 15–30% inhibition in tumor number (P < 0.05) (Fig. 1A). Over 80% of tumors developed in the distal part of the small intestine, explaining most of the result. The control and berry groups did not differ in the number of colon adenomas.


Figure 1
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  		FIGURE 1  Total number of adenomas (A), adenoma burden (B), and percentage of small (≤1.0 mm) and large (≥1.1 mm) adenomas (C) in the distal small intestine of Min/+ mice fed Con, BB, LB, or CB diets for 10 wk. Results are presented as box and whisker plots, n = 10–12 per group. *Different from Con, P < 0.05, Mann-Whitney U-test.

 
    Growth of adenomas. Only CB and LB inhibited adenoma growth (P < 0.05). Tumor burden was reduced by over 60% in mice fed both the berries in the distal small intestine (Fig. 1B). Compared to the Con, CB and LB resulted in a larger (P < 0.01) proportion of small adenomas (43, 69, and 64%, respectively) and a smaller proportion of large adenomas (56, 29, and 33%, respectively) (Fig. 1C). However, BB did not reduce tumor burden in the small intestine (Fig. 1B).

    Levels of ß-catenin and cyclin D1 in adenoma tissue. CB resulted in decreased levels of nuclear ß-catenin and cyclin D1 in the large adenomas (Fig. 2). The median level of nuclear ß-catenin tended to be lower (P = 0.065) in the CB group [2.70 (0.25–6.57), relative units] than in the Con group [5.16 (0.73–10.46)], whereas that of cyclin D1 was lower in former group [0.19 (0.00–0.66)] than in the latter [0.84 (0.16–2.26)] (P < 0.01). Even though LB did not reduce the level of nuclear ß-catenin, it resulted in a decrease in the level of cyclin D1 [0.32 (0.00–1.05)] compared to Con [0.84 (0.16–2.26) ] (P < 0.05). The levels of these 2 proteins were correlated with one another (r = 0.831; P < 0.001) and with the tumor burden [ß-catenin (r = 0.527; P < 0.001) and cyclin D1 (r = 0.732; P < 0.001)], indicating that ß-catenin and cyclin D1 in the tumor tissue are associated with the growth of the tumors.


Figure 2
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  		FIGURE 2  Representative immunoblots and the levels of nuclear ß-catenin (A) and cyclin D1 (B) in the large adenomas of Min/+ mice fed Con, BB, LB, or CB diets for 10 wk. In immunoblots, each band represents the median value of the group. Actin was used as a loading control. The levels of the nuclear proteins are presented as box and whisker plots, relative units, n = 10–12. *Different from Con, P < 0.05, Mann-Whitney U-test.

 
To further elucidate the role of ß-catenin and cyclin D1 in adenoma growth, we analyzed small and large adenomas separately. The levels of nuclear ß-catenin and cyclin D1 increased several-fold from the small to large adenomas in the Con, BB, and LB groups (Fig. 3A,B). However, CB prevented the increase in nuclear ß-catenin (P > 0.05; Fig. 3A) in the large adenomas [2.47 (0.00–5.85)] and actually maintained it at the level found in the small ones [2.10 (0.25–6.57)]. CB also inhibited the increase in nuclear cyclin D1, although it did not abolish it altogether (Fig. 3B). It is noteworthy that the variation in cyclin D1 values in large adenomas in the CB group was considerably less than in the other groups.


Figure 3
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  		FIGURE 3  Levels of ß-catenin (A) and cyclin D1 (B) in the small and large adenomas in Min/+ mice fed Con, BB, LB, or CB diets for 10 wk. Results are presented as box and whisker plots, n = 10–12. *Different from Con, P < 0.05, Wilcoxon's Signed Rank test.

 
Immunohistochemical staining of adenomas confirmed the ß-catenin and cyclin D1 results obtained in Western blotting analyses, but due to the small number of adenomas in IHC samples, the differences could not be tested statistically (Fig. 4A).


Figure 4
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  		FIGURE 4  Representative immunohistochemical staining of ß-catenin and cyclin D1 in the large adenomas of Min/+ mice fed Con, BB, LB, or CB diets for 10 wk (A; 400x magnification) and of ß-catenin, E-cadherin, and cyclin D1 in the normal-appearing mucosa of Con or CB mice (B; 100x magnification). Positive cells show brown staining.

 
    ß-Catenin, E-cadherin, and cyclin D1 were unaltered in the mucosa. The Con and berry groups did not differ in staining intensities of ß-catenin, E-cadherin, or cyclin D1 in the crypt or villus of the normal-appearing mucosa in our heterozygous Min/+ mice (Fig. 4B; Supplemental Table 1). The intensities of ß-catenin and E-cadherin were stronger in the crypt than in the villus in the different subcellular fractions in all groups (P < 0.05). Staining of cyclin D1 was predominantly nuclear in the proliferation zone of the crypt, while the villus had no staining of cyclin D1 (Fig. 4B).

    Affymetrix microarray reveals changes in genes related to colon cancer in the mucosa. We used the Affymetrix microarray approach to identify early changes in gene expression induced by the berries in the normal-appearing mucosa of Min/+ mice. One-way ANOVA indicated diet-induced changes in the expression of 377 genes. When the cut-off point was set at a 2-fold difference between the berry and Con treatments, the number of genes differing from the Con was 11 for BB, 25 for LB, and 10 for CB groups (Supplemental Table 2). The expression of the 2 genes adenosine deaminase and 5'ecto-nucleoditase (5-NT) were consistently and similarly decreased by all the berries (Fig. 5; Supplemental Table 2). LB feeding decreased expression of prostaglandin E2 receptor subtype EP4 compared to Con. The other changes seen were mainly in genes coding for immunoglobulins, genes for mixed functions, and unknown genes.


Figure 5
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  		FIGURE 5  Relative gene expression of ADA1 (A), ECTO (5-NT) (B), and Ep4 (C) by Affymetrix microarray in the normal-appearing mucosa of Min/+ mice fed Con, BB, LB, or CB diet for 10 wk. Each of the data points represents a value in a biological replicate chip of a pooled RNA sample from 3–4 mice. *Different from Con, P < 0.05, unpaired t test.

 

   Discussion
TOP
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
LITERATURE CITED
 
In this study, the use of 3 berries, BB, LB, and CB, with different phenolic profiles resulted in a significant reduction in the number of intestinal tumors in Min/+ mice. The major phenolic compounds in BB, LB, and CB are anthocyanins, proanthocyanidins, and ellagitannins, respectively (Table 1) (6,7). The anticarcinogenic effects of the berries could be explained by their high concentration of phenolics, which are known to inhibit several stages of carcinogenesis in vitro (1) and some also in vivo (26). Based on a subsequent experiment (27), we can exclude the possibility of ellagic acid being the main compound in CB to prevent adenoma formation. Interestingly, all berries decreased tumor number despite their different phenolic profiles, suggesting that the anticarcinogenic effects are not simply due to total amount of phytochemicals present. The effects seen may rather be a result of a mixture of compounds acting in synergy than an effect of a single active substance. Importantly, no adverse effects on weight gain by any of the berries occurred. Furthermore, contrary to some drugs (28), none of the berries increased tumor formation in the colon, indicating that chemopreventive components of the berries are likely to have a good safety profile. The amount of berries in the diets was high and could not be easily reached in a human diet. Therefore, a dose-response study is needed to determine the lowest level where chemoprevention can be achievable.

From a chemoprevention point of view, inhibiting the growth of existing tumors may be more important than preventing the initiating mutations, as has been proposed by Luebeck and Moolgavkar (29). In our study, CB and LB prevented the adenomas from growing large, resulting in a significantly larger proportion of small adenomas and a smaller proportion of large adenomas. CB and LB reduced the tumor burden over 60% and reduced both formation and growth of tumors, supporting their strong chemopreventive capacity.

An important finding is that CB and LB prevented the accumulation of nuclear ß-catenin and cyclin D1 in the large adenomas. Both ß-catenin and cyclin D1 have been associated with tumor growth and are recognized as targets for drug development (23,28). Nuclear ß-catenin correlates with tumor size (10) in colon cancer patients and loss of cyclin D1 in mice prevents the growth of intestinal lesions (30). Furthermore, both ß-catenin and cyclin D1 are associated with progression of colon tumorigenesis as nuclear ß-catenin increases from early adenomas to adenocarcinomas (9,10,31) and nuclear cyclin D1 increases from low-grade dysplastic adenomas to high-grade dysplasia (32). Consistent with these observations, the levels of ß-catenin and cyclin D1 in this study correlated with tumor burden and also with each other. The results suggest that CB and LB inhibit the growth of tumors by preventing the nuclear accumulation and, thus, presumably the transcriptional activity of ß-catenin, which leads to the decreased expression of cyclin D1. Decreased nuclear ß-catenin and cyclin D1 by CB and LB could be an important marker of their chemopreventive activity, because we found earlier that their expression is increased by diet-induced adenoma growth (M. Misikangas, H. Tanayama, J. Rajakangas, J. Lindén, A. Pajari, M. Mutanen, unpublished data) and also nonsteroidal anti-inflammatory drug elucidate their effects through this pathway.

Some chemopreventive compounds have been shown to change the levels of ß-catenin (33) and E-cadherin (34,35) in Min/+ mucosa in vivo and ex vivo. The effect of a loss of the Apc gene in the mouse intestine has been shown to differ between the crypt and villus compartments (36) and, therefore, we analyzed the levels of ß-catenin, E-cadherin, and cyclin D1 separately in the these 2 compartments. The lack of difference between the Con and berry diet groups in the staining intensities of these 3 proteins in the crypt and villus compartments indicates that the chemopreventive effect of the berries was not mediated through mucosal changes in these proteins.

We studied the normal-appearing Min/+ mucosa by Affymetrix microarray to identify early changes in intestinal tumorigenesis. Berry feeding resulted in relatively few over 2-fold changes in mucosal gene expression. All the berries decreased the expression of adenosine deaminase and 5-NT/CD73. These 2 enzymes are responsible for regulating tissue adenosine levels by degrading and generating adenosine, respectively. Their activity, along with adenosine levels, is increased in colon tumors (37,38), presumably as a result of local hypoxia (39). Importantly, adenosine has multiple tumorigenic effects (40–43), suggesting that inhibition of the adenosine pathway may have contributed to the anti-tumorigenic effects of the berries. The other noteworthy change was the decrease in the expression of the prostaglandin E2 receptor EP4, a modulator of colon carcinogenesis. Expression of this receptor increases with the progression of normal colonic epithelium to carcinoma (44) and its inhibition leads to decreased formation of intestinal adenomas in Min/+ mice by 31% (45). Our gene expression results are consistent with the inhibitory effects of the berries on tumor formation rather than explaining their effects on tumor growth, which was mainly reduced by CB.

To summarize, we have shown that berries have great potential as a source of chemopreventive components against intestinal tumorigenesis. The berries used in this study, BB, LB, and CB, resulted in significant reductions in tumor number in Min/+ mice. Importantly, 2 of these berries, LB and CB, also markedly inhibited the growth of the adenomas and accumulation of nuclear ß-catenin and cyclin D1. Affymetrix microarray on the normal-appearing mucosa revealed a reduced expression of genes involved in adenosine and prostaglandin metabolism, which could have contributed to the chemoprevention in this study. To fully utilize anticarcinogenic properties of berries, further studies should focus on the responsible constituents and their underlying mechanisms.


   FOOTNOTES
 
1 Supported by the Ministry of Agriculture and Forestry, the Innovation in Food Programme of the National Technology Agency of Finland, the University of Helsinki, the Finnish Cultural Foundation, and the Finnish Graduate School on Applied Bioscience. Back

2 Author disclosures: M. Misikangas, A.-M. Pajari, E. Päivärinta, S. E. Oikarinen, J. Rajakangas, M. Marttinen, H. Tanayama, R. Törrönen, and M. Mutanen, no conflicts of interest. Back

3 Supplemental Tables 1 and 2 are available with the online posting of this paper at jn.nutrition.org. Back

6 These authors contributed equally to this work. Back

7 Abbreviations used: Apc, adenomatous polyposis coli; BB, bilberry; CB, cloudberry; Con, control; LB, lingonberry; Min, multiple intestinal neoplasia; 5-NT, ecto-5'-nucleotidase; Tcf/Lef, T-cell factor/lymphoid enhancer factor. Back

Manuscript received 12 April 2007. Initial review completed 1 June 2007. Revision accepted 1 August 2007.


   LITERATURE CITED
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 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
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