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© 2008 American Society for Nutrition

Nutrition and Disease

Dietary Calcium and Cholecalciferol Modulate Cyclin D1 Expression, Apoptosis, and Tumorigenesis in Intestine of adenomatous polyposis coli1638N/+ Mice1,2

Kan Yang3, Sergio A. Lamprecht3, Hiroharu Shinozaki3, Kunhua Fan3, WanCai Yang4, Harold L. Newmark5, Levy Kopelovich6, Winfried Edelmann4, Bo Jin4, Claudia Gravaghi3, Leonard Augenlicht4, Raju Kucherlapati7 and Martin Lipkin3,*

3 Strang Cancer Research Laboratory, Department of Medicine (Gastroenterology and Hepatology), Weill Medical College of Cornell University, New York, NY 10065; 4 Albert Einstein College of Medicine, Bronx, NY 10461; 5 Department of Chemical Biology, Rutgers University, Piscataway, NJ 08854; 6 Division of Cancer Prevention, National Cancer Institute, NIH, Bethesda, MD 20892; and 7 Harvard Partners Center for Genetics and Genomics, Boston, MA 02115

* To whom correspondence should be addressed. E-mail: lipkin{at}mail.rockefeller.edu.


   ABSTRACT
TOP
 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 LITERATURE CITED
 
Both epidemiological and experimental findings have indicated that components of Western diets influence colonic tumorigenesis. Among dietary constituents, calcium and cholecalciferol have emerged as promising chemopreventive agents. We have demonstrated that a Western-style diet (WD) with low levels of calcium and cholecalciferol and high levels of (n-6) PUFA, increased the incidence of neoplasia in mouse intestine compared with a standard AIN-76A diet; models included wild-type mice and mice with targeted mutations. In the present study, adenomatous polyposis coli (Apc)1638N/+ mice carrying a heterozygous Apc mutation were fed either an AIN-76A diet, a WD, or a WD supplemented with calcium and cholecalciferol (WD/Ca/VitD3). Diets were fed for 24 wk and effects on cellular and molecular events were assessed by performing immunohistochemistry in colonic epithelium along the crypt-to-surface continuum. Feeding WD to Apc1638N/+ mice not only enhanced cyclin D1 expression in colonic epithelium compared with AIN-76A treatment as previously reported but also significantly increased the expression of the antiapoptotic protein B-cell lymphoma 2 (Bcl-2) concomitantly with a decrease in the proapoptotic Bcl2-associated X protein and the number of apoptotic epithelial cells. WD treatment enhanced mutant Apc-driven small intestinal carcinogenesis and also resulted in the formation of a small number of colonic adenomas (0.16 ± 0.09; P < 0.05). By contrast, the WD/Ca/VitD3 diet reversed WD-induced growth, promoting changes in colonic epithelium. Importantly, Apc1638N/+ mice fed the WD/Ca/VitD3 diet did not develop colonic tumors, further indicating that dietary calcium and cholecalciferol have a key role in the chemoprevention of colorectal neoplasia in this mouse model of human colon cancer.


   Introduction
TOP
 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 LITERATURE CITED
 
Many preclinical and clinical studies have indicated that components of Western diets can influence intestinal cancer incidence (1–4). Among these dietary constituents, calcium and vitamin D have emerged as promising chemopreventive agents (4,5).

In preclinical mouse models used in cancer etiology and prevention studies, tumor development has been increased by a Western-style diet (WD)8 containing low levels of calcium and cholecalciferol and increased (n-6) PUFA levels compared with a standard AIN-76A diet (6–9). Models studied have included both wild-type mice and mice with targeted mutations that induce intestinal and colonic cancer (6–10). In a previous study (11), we found that cyclin D1, a key cell cycle-related regulatory protein, was expressed in normal-appearing colonic and small intestinal epithelium and in intestinal adenomas of adenomatous polyposis coli (Apc)1638N/+ mice fed a standard AIN-76A diet for 24 wk. Cyclin D1 expression further increased in the mice fed WD for the same time period.

The present study extended our observations to Apc1638N/+ mice maintained on 3 different diets for 24 wk: AIN-76A, WD, and WD supplemented with calcium and cholecalciferol (WD/Ca/VitD3). We measured the effects of these diets on cyclin D1 expression, apoptosis, and tumor development in colonic epithelium.


   Materials and Methods
TOP
 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 LITERATURE CITED
 
Mice and diets

Fifty-one Apc1638/N+ mice (32 males, 19 females) carrying a heterozygous Apc mutation (12,13) were obtained from Drs. Kucherlapati and Edelmann's laboratories at 4–5 wk of age and were fed an AIN-76A diet (14) for 1–2 wk. At 6 wk of age, these mice were randomly divided into 3 groups and fed 1 of 3 diets: the AIN-76A diet group (n = 19, 9 males, 10 females); the WD diet (n = 19, 14 males, 5 females), a modified AIN-76A diet containing increased fat content in the form of corn oil and decreased levels of calcium and cholecalciferol; and the WD/Ca/VitD3 diet (n = 13, 9 males, 4 females), a modified WD with increased levels of calcium and cholecalciferol. Changes in the amount of these components in the experimental diets compared with the standard AIN-76A diet are shown (Table 1). The diets were formulated by Research Diets.


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  		TABLE 1 Composition of mouse Western diets1

 
All mice were housed (upper limit of 5 mice per cage) with ad libitum access to water and food and were maintained on a 12-h-light/-dark cycle in a controlled-temperature room in the Laboratory Animal Research Center at the Rockefeller University, an American Association of Laboratory Animal Care facility complying with USDA regulations and NIH Guidelines for the Care and Use of Laboratory Animals. The mice were weighed every week. After 24 wk of feeding, mice were killed with CO2 and the complete gastrointestinal tract was removed.

Processing flat colonic mucosa and evaluating tumor formation

Two segments of flat mucosa were taken from the distal colon and fixed in 10% buffered formalin or in 70% ethanol, respectively, and processed. The remaining gastrointestinal tract was then opened longitudinally, except for the stomach, which was cut along the greater curvature and fixed in 10% buffered formalin. The specimens collected were examined for tumors under a dissecting microscope. We recorded number of tumors, size, and location. Tissue sections (4 µm) were made from tissues fixed in formalin, paraffin-embedded, and stained with hematoxylin and eosin for histological diagnosis. Tissue sections made from ethanol-fixed specimens were used for Bcl-2 and Bax assays.

    Assays of cyclin D1, Bax, and Bcl-2. Cyclin D1, Bax, and Bcl-2 expression was evaluated by immunohistochemistry in flat colonic mucosa. For assessment of cyclin D1 expression, a mouse monoclonal antibody was purchased from Novocastra Laboratories. This antibody does not cross-react with cyclin D2 and D3 (10). The antibodies to Bax and Bcl-2 were rabbit anti-mouse antibodies purchased from Santa Cruz Biotechnology and Pharmingen, respectively. The immunoassay method has been described previously in detail (11).

Measurements of epithelial cells in the flat colonic mucosa were made on well-oriented colonic crypts in which the full length of crypts and crypt lumen were visible. Twenty-five colonic crypts (50 crypt columns) were scored for each mouse.

A 5-grade semiquantitative scoring system was used to record positive cells for Bcl-2 or cyclin D1 (11). Whole crypt columns and each crypt compartment were scored for 1 of the following 5 grades according to number of positive cells: 0, no cells positive; 1, positive cells less than negative cells; 2, equal number of positive and negative cells; 3, positive cells more than negative cells; and 4, all cells positive. The number of Bax positive cells was determined as described by Yang et al. (15).

Morphological assessment of apoptosis

Apoptosis originated as a morphological phenomenon, and the number of apoptotic cells was measured based on morphologic features previously described (15). Briefly, these included a single condensed cell or a cluster of apoptotic bodies inside another healthy (host) cell, with or without a halo around the apoptotic body. Measurements were conducted on well-orientated crypts in flat colonic mucosa. Fifty colonic crypt columns were examined in each mouse.

Statistical analysis

The data are presented as means ± SEM. We used 1-way ANOVA and Kruskal-Wallis 1-way ANOVA test to compare the 3 diet groups for tumor incidence and tumor multiplicity. The Mann-Whitney test was used to compare significance between control and study groups. Differences were considered significant when P-value was <0.05.


   Results
TOP
 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 LITERATURE CITED
 
Body weight

At 6 wk of age, body weights did not differ among the AIN-76A (16.2 ± 1.1 g), WD (16.3 ± 0.8 g), and WD/Ca/VitD3 (17.0 ± 0.5 g) groups. Body weights increased in all groups and after 4 wk, that of the WD group (35.6 ± 2.3 g) did not differ from the WD/Ca/VitD3 group (33.2 ± 1.7 g), but it was lower than that measured in other groups (27.9 ± 1.5 g; P < 0.05).

Cyclin D1 expression

Apc1638N/+ mice fed WD for 24 wk had enhanced colonic cyclin D1 levels in whole colonic crypt compared with AIN-76A P < 0.001 (Fig. 1A). Adding calcium and cholecalciferol to AIN-76A resulted in lower cyclin D1 expression to a level comparable to that of the mouse group fed unmodified AIN-76A (Fig. 1A). The WD-induced increase in cyclin D1 expression in upper colonic crypts (Fig. 1B) was markedly decreased (P < 0.001) in mice fed either AIN-76A or WD/Ca/VitD3 diets. Microphotographs (Fig. 2) show a representative example of dietary modulation of cyclin D1 expression in colonic epithelial cells of an Apc1638N/+ mouse. The immunochemical expression of cyclin D1, which extended from the crypt base to the mucosal surface in Apc1638N/+mice fed WD (Fig. 2A), was markedly reduced in mice maintained on the WD/Ca/VitD3 dietary regimen (Fig. 2B).


Figure 1
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  		FIGURE 1  Cyclin D1 expression score per crypt column (A) and crypt compartments (B) in colonic mucosa of Apc1638N/+ mice fed AIN76A (n = 10), WD (n = 11), and WD/Ca/VitD3 (n = 10) diets. Ms, Mucosal surface; uc, upper crypt compartment; mc, middle crypt compartment; lc, lower crypt compartment. Cyclin D1 expression scores are means ± SEM of immunopositive cells (see "Materials and Methods"). *Different from control (AIN-76A), P < 0.05; **P < 0.01; ***P < 0.001.

 

Figure 2
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  		FIGURE 2  Representative microphotographs of cyclin D1 expression in colonic crypts of Apc1638N/+ mice fed WD (A) or WD/Ca/VitD3 (B), respectively, for 24 wk (400x magnification).

 
Apoptosis

    Morphological evaluation. The number of apoptotic cells in the flat colonic epithelium of Apc1638N/+ mice fed the WD was markedly lower compared with mice fed the AIN-76A diet for the same time period (P < 0.01; Fig. 3). In contrast, the number of colonic surface cells with morphological signs of apoptosis in mice fed the WD/Ca/VitD3 diet was higher compared with WD-treated mice (P < 0.05), although lower than that scored in colonic cells of Apc1638N/+ mice fed AIN-76A alone (Fig. 3).


Figure 3
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  		FIGURE 3  Apoptotic cells in colonic crypt compartments of Apc1638N/+ mice fed AIN-76A (n = 10), WD (n = 11), and WD/Ca/VitD3 (n = 10) diets. Values are expressed as means ± SEM. *Different from control (AIN-76A), P < 0.05; **P < 0.01; ***P < 0.001.

 
    Expression of anti-apoptotic Bcl-2 and pro-apoptotic Bax proteins. Immunohistochemical expression of the anti-apoptotic protein Bcl-2 in WD-fed Apc1638N/+mice was greater (Fig. 4A) in whole colonic crypt columns compared with AIN-76A-treated mice (P < 0.05). The same trend (P < 0.05) was found at the mucosal crypt surface and in the upper (P < 0.01) and middle (P < 0.05) crypt compartments (Fig. 4B). In contrast, treatment with WD/Ca/VitD3 markedly reduced Bcl-2 expression at the surface of colonic crypts (P < 0.001) and along the upper (P < 0.01) and middle (P < 0.05) crypt zones.


Figure 4
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  		FIGURE 4  Expression of the antiapoptotic protein Bcl-2 in flat colonic mucosa of Apc1638N/+ mice fed AIN-76A (n = 10), WD (n = 11), and WD/Ca/VitD3 (n = 10) diets. Values are means ± SEM. (A) Number of immunopositive Bcl- 2 cells per colonic crypt column and (B) immunopositive Bcl-2 cells in various colonic crypt compartments. *Different from control (AIN-76A), P < 0.05; **P < 0.01; ***P < 0.001.

 
In contrast to enhanced Bcl-2 expression in Apc1638N/+ mice fed WD, expression of the pro-apoptotic protein Bax in colons of mice was markedly lower compared with that observed in mice fed the AIN-76A diet (P < 0.05; Fig. 5A); the WD-induced decrease in Bcl-2 expression, (P < 0.01; P < 0.05) was reversed in Apc1638N/+ mice maintained on the WD/Ca/VitD3 diet (Fig. 5A). Bax expression increased with this dietary treatment in colonic surface cells and upper crypt cells.


Figure 5
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  		FIGURE 5  Proapoptotic Bax positive cells in flat colonic mucosa of Apc1638N/+ mice fed AIN-76A (n = 10), WD (n = 11), and WD/Ca/VitD3 (n = 10) diets. Values are means ± SEM, n = 10. (A) The number of immunopositive Bax cells per colonic crypt column; (B) the distribution of cells in various colonic crypt compartments. *Different from control (AIN-76A), P < 0.05.

 
Tumor formation

In the small intestine, where tumors characteristically occur in Apc1638N/+ mice, WD treatment resulted in tumor incidence of 95% compared with 68% in mice fed the AIN-76A diet. Tumor formation, however, declined sharply to 11% in mice fed the WD/Ca/VitD3 diet. Tumor multiplicity after the WD was 3.00 ± 0.43 tumors/mouse compared with 1.47 ± 0.46 (P < 0.01) in the AIN-76A mouse group and 2.15 ± 0.44 (P < 0.02) in mice fed WD/Ca/VitD3 (n = 13). Tumor volume per mouse increased compared with AIN-76A, 67.0 mm3 vs. 18.0 mm3 (P < 0.001); in the group fed the WD/Ca/VitD3 diet, the tumor volume decreased to 20.4 mm3 (P < 0.01 vs. AIN-76A).

In Apc1638N/+ mice fed AIN-76A for 24 wk, no colonic tumors developed; however, adenomas were found in the cecum of mice maintained on WD for the same time period. Tumor incidence was 11%, multiplicity was 0.16 tumors/mouse, and tumor volume was 0.4 mm3/mouse. No tumors developed in the colon of the Apc1638N/+ mice fed the WD/Ca/VitD3 diet.


   Discussion
TOP
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
LITERATURE CITED
 
Several new findings are reported in this study in response to various diets fed to Apc1638N/+ mice. Sustained WD feeding not only enhanced cyclin D1 expression in normal-appearing flat colonic epithelium as reported earlier (11), but it also significantly increased the expression of antiapoptotic protein Bcl-2 concomitantly with decreased expression of proapoptotic protein Bax and decreased the number of colonic epithelial apoptotic cells. WD treatment also resulted in the formation of colonic adenomas and a carcinoma. In contrast, WD/Ca/VitD3 administration blunted WD growth-promoting cellular and molecular changes in colonic epithelial cells; importantly, mice fed the WD/Ca/VitD3 diet did not develop colonic adenomas or carcinomas.

As shown previously (11) and in the present report (Fig. 1), Apc1638N/+ mice fed an AIN-76A diet expressed cyclin D1 in colonic epithelium. The enhanced expression of cyclin D1, a key cell cycle protein involved in the control of cell replication (16) and overexpressed in colonic tumors (17,18), occurred mostly at the colonic mucosal surface, where differentiated epithelial cells are normally located. Misplaced expression of cyclin D1 may reflect expansion of the crypt proliferative compartment, a hallmark of early-stage colonic tumorigenesis (19). Consonant with this view, Mariadson et al. (20) reported that the differentiation process of normal mouse intestinal epithelial cells is associated with downregulation of cyclin D1 expression.

The involvement of wild-type APC in maintaining apoptosis in colonic tissue has been proposed (21) but remains controversial (22). Previous observations have shown that in Apc1638N/+ mice fed a standard AIN-76A diet, the Apc mutation does not necessarily lead to alteration in apoptosis frequency compared with that measured in normal mouse colon (23). In the present study, apoptosis in Apc1638N/+ mice occurred predominantly in the colonic mucosal surface, where spontaneous physiological apoptosis is also observed in the wild-type mouse. This observation is in agreement with predominant expression of proapoptotic Bax protein in the colonic mucosal surface cells. An expression gradient of Bcl-2 was observed along the colonic crypt continuum of Apc1638N/+ mice (24). Although it was reported in earlier studies that Bcl-2 in the wild-type mouse was typically localized at the base of colonic crypts, recent reevaluation of findings indicates variable expression of the antiapoptotic protein in mouse large intestine (25).

No colonic tumors were found in Apc1638N/+ mice maintained on a standard AIN-76A diet for 24 wk. The addition of calcium and cholecalciferol to WD blunted colonic cyclin D1 expression, enhanced the apoptotic process, and prevented intestinal tumorigenesis. Consistent with these results are previous experimental observations showing that cholecalciferol and calcium modulate cyclin D1 expression, apoptosis, and tumorigenesis in intestinal and colonic tissues (4,26). An extensive review of cholecalciferol regulation of signaling pathways and cancer prevention has been published recently (27).

We have proposed [reviewed in (4)] that growth-restraining and differentiation- and apoptosis-inducing actions of dietary calcium on intestinal tumor cells is mediated, at least in part, by the calcium-sensing receptor (CaSR). Consonant with this view, Chakrabarty et al. (28) have presented evidence for the involvement of extracellular calcium and CaSR in differentiating human colonic tumor cells. A recent finding was the intriguing observation (29) that both extracellular calcium and/or 1{alpha}-25-dihydroxyvitamin D3 stimulated CaSR promoter activity in human colonic tumor cells, implying direct cross-talk between vitamin D and calcium at the level of the CaSR promoter.

No data are available pertaining to an action of calcium on colonic cyclin D1 expression/activity. However, it may be noted here that calcium interference with the formation of cyclin D1-CDK4 complex and with cyclin D1 synthesis has been shown in cells of epithelial lineage (30), which require calcium to sustain their differentiation program.

Whereas WD feeding led to decreased apoptosis in colonic cells, the WD/Ca/VitD3 diet enhanced the apoptotic process and this stimulatory effect was mechanistically associated with decreased expression of the anti-apoptotic Bcl-2 protein and increased expression of the pro-apoptotic Bax protein.

These findings are consistent with previous studies indicating that vitamin D and calcium modulate the apoptotic process in several mammalian cells, including colon cancer cells (4,26,27,31–33). Vitamin D has been shown to control expression of members of the Bcl-2 family known to play a major role in the signaling cascades of apoptosis. Thus, vitamin D downregulates the expression of Bcl-2, the prototypical antiapoptotic protein, and upregulates proapoptotic Bax protein in a number of cells, including cells of the large intestine (4,26,27,32,33). This action would conceivably tilt the critical ratio of pro-and antiapoptotic proteins of the Bcl-2 family members in favor of the death pathway.

A central role of calcium in regulating cell death has been long recognized (34–36) and calcium has been identified as a messenger coordinating mitochondrial-endoplasmic reticulum interactions to promote apoptosis. Thus, release of calcium from IP3 receptors induced by cytochrome c was shown to provoke a "mass exodus" of cytochrome c from mitochondria by a feed-forward mechanism, followed by activation of effector caspases and nuclear enzymes that hasten cell death (37).

Both WD and WD/Ca/VitD3 diets used in the present study contain high levels of corn oil, which is rich in (n-6) PUFA linoleic acid, an obligatory precursor of arachidonic acid. Enhanced synthesis of arachidonic acid in Apc1638N/+ colonic cells may ultimately lead to increased production of prostaglandin E2 (PGE2), a key eicosanoid that promotes colorectal carcinogenesis (38). Of note, PGE2 was recently shown to increase cyclin D1 expression in ApcMin/+ mouse polyps and to stimulate β-catenin/TCF transcription in colon cancer cells (39). If PGE2 promoted colonic tumor formation in Apc1638N/+ mice fed WD, this tumorigenic PGE2 effect was suppressed in this diet by supplementing with cholecalciferol and calcium (this study).

In summary, our results show that normal-appearing large intestine epithelium of Apc1638N/+ mice, composed exclusively of cells heterozygous for Apc, underwent subtle molecular changes that are hallmarks of cell transformation. These changes, however, were not sufficient to induce tumor formation in mice fed a normal AIN-76A standard diet for 24 wk. In contrast, feeding mice a WD, low in dietary cholecalciferol and calcium, not only further perturbed the growth of colonic cells but also ultimately resulted in tumor formation. Supplementation of WD with cholecalciferol and calcium suppressed WD-induced tumorigenesis, further strengthening the view that these micronutrients play an important role in chemoprevention of intestinal cancers.


   FOOTNOTES
 
1 Supported by NCI awards N01-CN-43302, N01-CN-43308, U54-CA100926, CA84301, and ES-11040. Back

2 Author disclosures: K. Yang, S. A. Lamprecht, H. Shinozaki, K. Fan, W. Yang, H. L. Newmark, L. Kopelovich, W. Edelmann, B. Jin, C. Gravaghi, L Augenlicht, R. Kucherlapati, and M. Lipkin, no conflicts of interest. Back

8 Abbreviations used: Apc, adenomatous polyposis coli; Bax, Bcl2-associated X protein WD; Bcl-2, B-cell lymphoma 2; CaSR, calcium-sensing receptor; PGE2, prostaglandin E2; WD, Western-style diet; WD/Ca/VitD3, Western-style diet supplemented with calcium and cholecalciferol. Back

Manuscript received 11 February 2008. Initial review completed 31 March 2008. Revision accepted 26 June 2008.


   LITERATURE CITED
TOP
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
 LITERATURE CITED
 

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