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Symposium

Dietary Components Modify Gene Expression: Implications for Carcinogenesis¹

Albert Einstein Cancer Center, Montefiore Medical Center, Bronx, NY 10467 and ^* Strang Cancer Prevention Center, New York, NY

²To whom correspondence should be addressed. E-mail: augen{at}aecom.yu.edu.

ABSTRACT

Mouse genetic models that probe important pathways in intestinal cell maturation, such as cell-cycle regulation, apoptosis, and, especially, lineage specific differentiation, have provided profound insight into the underlying mechanisms of intestinal tumor formation and progression. However, a wealth of epidemiological and experimental data indicates that environment, especially the diet, is a principal determinant of relative risk for tumor development. We have demonstrated that even in mouse models in which tumor incidence is strongly initiated by genetic manipulation of genes, such as Apc, p21^WAF1/cip1, and p27^Kip1, a Western-style diet that is high in fat and low in calcium and vitamin D can dramatically increase and accelerate tumor formation. Moreover, experiments show that modulation of calcium and vitamin D levels can substantially influence tumor formation in both the mouse genetic models, as well as in a new dietary model that appears to mimic the development of sporadic colon cancer. Finally, analysis of gene expression profiles provides important insights into how diets may alter metabolic profiles and regulatory pathways that influence probability of tumor formation in the histologically and physiologically normal intestinal mucosa.

KEY WORDS: • Western-style diet • gene expression • colon cancer

Epidemiological studies have identified diet as a major variable that accounts for organ-site specific differences in incidence of cancer in patient populations in different countries and geographical areas. For colon cancer, these differences in incidence are profound. Moreover, there are several examples of migrant populations that clearly link these differences in incidence to environmental factors. For example, native Japanese historically had a relatively low incidence of colon cancer relative to stomach cancer. Upon migration to the Hawaiian Islands, within one generation, this relative incidence begins to shift, and, within 2 generations, the incidence of colon cancer is nearly equivalent to the high rate of the U.S. white population. Thus, within 2 generations, there is almost an order of magnitude shift in the relative incidence of colon cancer. Two generations is far too short a time for the genetics of the population to have shifted significantly, clearly demonstrating that environmental factors—most likely diet—account for this dramatic change. Confirmation of this is the fact that as the citizens of Japan have adopted a more Western-style diet, their incidence of colon cancer has begun to increase relative to the historically lower levels. To put this in a practical context, such data indicate that it is theoretically possible to reduce colon cancer incidence by at least 50%, and possibly closer to 90%, by shifts in diet. If this could be realized, this would be an astounding advance in preventing this major disease.

There is a wealth of data from rodent model systems, both chemically, as well as genetically induced intestinal cancer, that demonstrate the profound influence of diet on cancer initiation and progression. There is still, however, a reluctance on the part of most molecular and cell biologists to accept this as fundamental to the process of tumorigenesis. We believe there are 2 reasons for this. First, there is a fundamental misconception that diet may only play a role in establishing risk for tumor formation in those without genetic predisposition. However, there are both population data and experimental data that indicate this is not correct. For example, hereditary nonpolyposis colorectal cancer is an inherited syndrome that imposes a very high risk for development of intestinal cancer in affected families. However, it is instructive to note that in the original studies of this familial cancer syndrome by Warthin in the early 1900s, cancer family "G" had a high incidence of gastric cancer, which was also the principle sporadic gastrointestinal cancer in the United States at that time (1). By mid-century, when family "G" was revisited by Lynch, gastrointestinal cancer in this family was still high but had shifted in site to colon cancer, which had replaced gastric cancer as the principle site of sporadic intestinal cancer (2). Thus, the genetics of the family (i.e., inheritance of a mutant gene involved in DNA mismatch repair) dictated high cancer incidence, but the environment (i.e., diet) was responsible for dictating site specificity. We will also present data that demonstrate that in every mouse genetic model in which intestinal cancer is initiated at a very high frequency by inherited genetic mutations, dietary factors still exert a profound effect on tumor frequency and size, and, in some cases, site of formation. Therefore, even when high incidence is dictated by genetic factors, dietary effects can be manifest in terms of modulation of tumor frequency or size. In terms of clinical management, there are high-genetic-risk individuals for whom this may not be relevant. For example, in patients with familial adenomatous polyposis who develop hundreds of polyps, dietary alterations may decrease this number significantly, but even a 50% decrease in polyp number would not dictate changes in clinical care. However, this does not alter the fact that diet can play a profound role in the penetrance of the disease on a per tumor basis.

The second reason for the lack of attention among molecular biologists to the importance of diet is the difficulty in attributing dietary alterations in probability of tumor formation to specific biochemical and molecular alterations. Consider that for the 90% of colon cancers diagnosed in the United States termed sporadic colon cancer, the elevation of the probability of tumor formation by dietary factors may involve subtle affects on the intestinal mucosa that are integrated over 6 to 7 decades of life. During this time, there are 10¹² cell divisions in the mucosa and even under the influence of diets that elevate risk significantly, generally a single tumor forms. During this period of over 6 decades, the intestinal mucosa essentially functions normally and exhibits no pathology. We are therefore faced with the fact that there are very subtle shifts in physiology and metabolism that may increase the probability of only 1 of 10¹² cell divisions undergoing a change leading to neoplasia. Further, altered cells must also be retained in the mucosa, rather than being sloughed into the lumen, or undergoing apoptosis or anoikis. It is therefore difficult to design experiments to identify alterations that may be of significance. As regards to this, K. Yang, H. Newmark, and M. Lipkin (Strang Cancer Prevention Center; unpublished results) have developed a new model of rodent colon cancer modulated by diet that we believe mimics the generation of human sporadic intestinal cancer. We will discuss data on altered pathways that may perturb intestinal homeostasis in this model and thus establish an increased probability of tumor formation.

Dietary interaction with genetic factors in intestinal tumor formation

We have used 2 versions of a Western-style diet (WD)³ to investigate the interaction of dietary and genetic factors in the mouse (see Table 1). The original WD was formulated by Newmark and Lipkin to mimic major risk factors for intestinal cancer in developed countries, particularly in the United States (3–5). This diet is high in fat and low in calcium and vitamin D. It is important to note that these levels are within the normal range of these components in the U.S. diet. Thus, based on nutrient density, the levels of calcium and vitamin D are at the low end of the normal range but are not "deficient" diets that raise other overt health problems for the mice or for individuals who consume such diets. The second WD we use (new Western Diet; NWD) has these same high levels of fat and low calcium and vitamin D, but also incorporates lower levels of fiber and compounds that contribute to the single carbon, "methyl donor" pool: folate, methionine, and choline (6). Lower intakes of these nutrients have each been linked to higher risk of colon cancer in the U.S. population.

More recently, we have turned our attention to another cdki, termed p27^Kip1. While it had been reported that inactivation of p27 in mice that harbor a mutant Apc allele was effective in enhancing tumor formation (9), we, in fact, found that inactivation of p27 alone was sufficient to cause intestinal tumor formation in mice (10). We have subsequently found that this is strictly a function of diet: on a standard laboratory diet, used by most investigators, no tumors form in mice that are p27^+/+, and very few tumors form in p27^{± or –/–} mice. However, when fed a defined AIN76A diet, tumor formation is significant for these latter 2 genotypes and increases even further in the same animals fed the WD (W. C. Yang, K. Bancroft, and L. Augenlicht, Albert Einstein Cancer Center; unpublished results). The lack of tumor formation in the animals fed the diet may be due to inhibitory phytochemicals in this plant-based diet. Alternatively, the AIN76A diet, designed to maximize growth of the mice, may be considered a tumor promoting diet. In either case, the profound affect of dietary factors on tumor formation is apparent. Moreover, not only do Apc^±, p27^{± or –/–} mice on the AIN76A and WD diet form tumors but they also exhibit intussusception, a pathology seen in patients with intestinal tumors, but not reported in mouse models (W. C. Yang, K. Bancroft, and L. Augenlicht, Albert Einstein Cancer Center; unpublished results). Finally, in every mouse model of intestinal cancer that we or our collaborators have investigated, including models involving defects in mismatch repair alone or coupled with inherited Apc mutations, the WD increased tumor formation and generally produced more tumors in the large intestine (K. Yang and M. Lipkin, Strang Cancer Prevention Center; unpublished results). Therefore, it is clear that it is necessary to consider dietary factors to accurately model human intestinal cancer, as well as to maximize tumor formation in such models.

A new mouse model of sporadic colon cancer

Newmark et al. (6) reported that the NWD was capable of causing preneoplastic, as well as some neoplastic lesions, when fed to wild-type mice for more than 1 y. This has been studied further by them in an experimental design in which C57Bl/6J control mice were maintained, upon weaning, on either an AIN76A diet or the NWD diet. Moreover, since supplementation of the WD with calcium and vitamin D had been shown to reverse the increased tumor formation stimulated by the WD in Apc1638^±, Apc^Min/+, and Apc^±,Mlh1^± mice (K. Yang, Strang Cancer Prevention Center; W. Edelmann, Albert Einstein College of Medicine; R. Kucherlapati, Harvard Medical School; and M. Lipkin, Strang Cancer Prevention Center; unpublished results), a mouse group that was fed the NWD supplemented with calcium and vitamin D was also included. After 2 y on the NWD, mice developed a significant number of colon and small intestinal tumors (both adenomas and adenocarcinomas), which was not seen when the NWD was supplemented with calcium and vitamin D (K. Yang and M. Lipkin, Strang Cancer Prevention Center; unpublished results). The incidence and the number of colon tumors, kinetics of tumor development (i.e., at about 80% of the life span of the organism), and dependence of tumor formation on major risk factors for colon cancer in the Western diet are all remarkably similar to the development of sporadic colon cancer in the human population.

In the same experiment, mice from each dietary group were euthanized at 3 mo for analysis of molecular changes in colon epithelial cells that might predispose the animals for development of pathological changes at the later time points. This time point was chosen because it was sufficient for the diets to have influenced metabolism and physiology that establish a relative risk for tumor development but early enough so that small tumors and microadenomas that presage tumor development at 18–24 mo would not yet be a complicating factor in analysis.

In comparing colonic RNA from animals maintained on the NWD to those fed the control AIN76A diet, about 15% of 28,000 sequences were altered in expression. This altered profile of gene expression in the colon induced by the NWD compared with the AIN76A diet was partially shifted back by supplementation of the NWD with calcium and vitamin D toward the profile of expression seen in the control diet. In fact, we were able to identify over 700 sequences altered in expression by the NWD that were significantly shifted back by addition of calcium and vitamin D toward their expression levels in the AIN76A fed animals. Thus, there is a subset of sequences that closely track the levels of calcium and vitamin D in the diet, as well as the relative risk for tumor development.

Grouping these sequences into functionally related categories revealed significant enrichment among sequences altered in expression for genes involved in 36 of 133 predefined functional groups. For example, the profile of expression of genes involved in lipid metabolism was altered by the NWD, consistent with the elevated fat content of this diet. Remarkably, elevation of calcium and vitamin D in the NWD partially restored the pattern of expression of these genes to that seen in the control diet, even though no change was made to the lipid content of the diet. Thus, calcium and vitamin D appear to normalize the metabolic profile of the cells with regard to lipid metabolism. There were also extensive changes in expression of genes associated with calcium homeostasis, again consistent with the differences in calcium levels in the different diets.

One of the most interesting set of changes involved genes involved in Wnt signaling, the pathway that is at the center of initiating colon tumor formation in both the human and in the mouse genetic models. Wnt signaling is a developmental pathway that, when activated in the intestinal tract, favors the dissociation of ß-catenin from E-cadherin in the membrane and therefore the association of ß-catenin with Tcf4, a member of a family of transcription factors (11,12). This forms an active transcription complex that initiates a program of altered gene expression. This program has been shown to be associated with the regulation of genes involved in cell cycling, such as c-myc and cyclin D1, as well as cell differentiation (13–15). In fact, it has been demonstrated that Wnt signaling maintains cells in a "crypt progenitor" like phenotype (14) and that in the constitutive absence of this signaling, when cells are forced to express a dominant-negative Tcf4 or in mice with a targeted inactivation of Tcf4, the stem-cell population differentiates, and the mucosa degenerates (16).

In colon cancer, ß-catenin-Tcf signaling becomes constitutive. A key regulatory element in the Wnt pathway is the APC gene product. This protein forms a complex with ß-catenin, axin, and GSK3ß to target ß-catenin for phosphorylation, and subsequent ubiquitination and proteosomal degradation (11,15,17). Thus, ß-catenin-Tcf signaling is regulated in part by the APC gene product. In the development of colon cancer, APC (or less frequently, ß-catenin itself) is mutated, either in the germ line or somatically, and this regulatory step is therefore abrogated (11,15,17). Thus, ß-catenin-Tcf signaling becomes constitutively activated, leading to cell cycling and persistence of cells in a crypt progenitor-like phenotype (i.e., undifferentiated or partially differentiated), and eventually, causing tumor formation.

When mice were fed the NWD, there was an elevation of expression of ß-catenin gene expression. Thus, cells may have been driven toward a more proliferative, less differentiated state. However, when mice were fed the NWD diet supplemented with calcium and vitamin D, the level of expression of the ß-catenin gene decreased, reestablishing a measure of regulation of the pathway. Further, when mice were fed the NWD, there was increased expression of genes that encode receptors for Wnt signals, which decreased when the NWD was supplemented by calcium and vitamin D. Therefore, there may be subtle changes in how the pathway responds to Wnt ligands and hence in homeostasis of the intestinal mucosa. In summary, diet appeared to modulate the key pathway that leads to colon tumor formation. Moreover, this could be related to extensive changes in both the redox and the cytoskeleton functional groups. It has recently been demonstrated that ß-catenin also regulates an oxidative stress pathway, which results in decreased cell proliferation (18,19). Therefore, ß-catenin regulated pathways may interact as positive and negative modulators of cell cycling to maintain homeostasis of the intestinal mucosa. As is clear from the development of tumors in animals maintained on the Western-style diet [interestingly, originally termed a "stress diet" by Newmark and Lipkin (3,7)], this drive to maintain homeostasis eventually fails, at least in some crypts, perhaps because of an imbalance in these pathways generated by the complexity of changes in both Wnt signaling and in redox functions. This may be reflected in alterations in expression of genes involved in cell-cycle progression. Finally, extensive changes in genes that encode proteins linked to cytoskeleton structure and function could also stem from the alterations in Wnt signaling, because their normal binding partners in the membrane, the cadherins, connect to the cytoskeleton (20). This may be of significance in neoplastic transformation because cell shape changes may affect cell-cell and cell-matrix interactions and signaling, and such changes in the cytoskeletal network have long been recognized as a hallmark of cancer.

Pathways of maturation in the intestinal tract

As discussed above, dietary modulation of the probability of tumor development would be expected to affect pathways that govern normal cell maturation. These would include pathways that regulate and coordinate cell proliferation, cell migration, apoptosis/anoikis, and lineage-specific differentiation. There is certainly much information available regarding the role of key molecules in these maturation pathways, both in general and specifically for intestinal epithelial cells. To expand our knowledge of how cells mature during their migration from the crypt to the lumen, we have adapted the Weiser technique (21,22) to the mouse to fractionate cells according to their position within this continuum. This method involves progressive dissociation of cells from the small intestine, beginning from the top of the villus (fraction 1) and proceeding down to the crypt (fraction 10). We have validated the fractionation in several ways (23): the expression of differentiation markers, such as villin and alkaline phosphatase, increase as a gradient from fraction 10 (bottom) to fraction 1 (top), and PCNA, a marker of proliferating cells, decreases along this axis, and is undetectable by approximately fraction 5. We have also done gene expression profiling of these fractions. This further validated the fractionation, as other differentiation markers also increased as cells migrated upward, and there was a good relation between sequences that changed in expression as cells migrated up from the crypt and sequences we had previously identified during the cell-cycle arrest and differentiation along the absorptive cell lineage of Caco2 cells in culture (24). Moreover, several sequences characteristically expressed in Paneth cells, which migrate down into the crypt base, were maximally expressed in the crypt fractions, as were a large number of cyclins and cyclin-dependent kinases, which drive the cells through the cell cycle. We have now compared the database of sequences altered in expression by the NWD diet to other gene expression databases we have generated (www.augenlichtlab.com). We found that a significant percentage of sequences altered in expression by diet are sequences that also change in expression during migration of the cells along the crypt-lumen axis (G. Corner and L. Augenlicht, Albert Einstein Cancer Center; unpublished results). This is further evidence that the diets are likely altering homeostasis in the intestinal mucosa, at the molecular as well as the cellular level.

A key role of c-myc and p21WAF1/cip1

A particularly interesting pathway that governs cell maturation and which is regulated by Wnt signaling, encompasses the c-myc and the p21^WAF1/cip1 gene, a cyclin-dependent kinase inhibitor. As discussed, c-myc is a target of ß-catenin-Tcf4 transcriptional regulation (25), and, in the lower portion of the crypt where ß-catenin-Tcf4 signaling is highest, expression of c-myc is also high. Moreover, we have shown that c-myc decreases as cells migrate up the crypt, and coincident with this is an altered regulation of a large number of genes that have been shown to be c-myc targets (23). Thus, we believe that c-myc is a major element in stimulating the cascade of events that govern normal intestinal cell maturation. Further, p21 is one of the important genes that c-myc regulates in this cascade. The expression of p21 is repressed by c-myc forming a complex with a positive regulator of p21, Miz-1. Upon decreased expression of c-myc, Miz-1 becomes free to bind to and activate the promoter of p21, thus elevating p21 expression (14). In investigating the relative levels of c-myc and p21 mRNA expression along the crypt-lumen axis, we found that c-myc progressively decreases from fraction 10 (crypt) to fraction 1 (top), while p21 levels are not elevated until the cells clearly exit the crypt (23). Thus, the ratio of p21 to c-myc mRNA increases "stepwise" along this axis: due to the drop in c-myc, the p21/c-myc ratio is elevated as cells migrate up the crypt. This plateaus immediately until cells are in the villus. Then, as p21 is elevated, there is a further increase in the p21/c-myc ratio nearer the top of the crypt.

This pattern needs to be confirmed at the protein level and by more careful positioning of the changes along the crypt-villus axis. However, it may indicate an integration of the cell maturation inducing affects of c-myc and p21 along this axis, coordinated by the stoichiometry of the components. This may be critical, because, as discussed above, inactivation of p21 can increase tumor formation initiated by inactivation of Apc. Interestingly, the fact that inactivation of p21 is not sufficient for tumor formation [i.e., in the intestine, inactivation of p21 also required a mutation of Apc for tumor formation (8)] may be because p21 is not normally expressed in either the stem-cell or the transit-cell population in the crypt but only as cells have migrated into the villus. In this context, it is interesting to note that we have recently detected that for the cdki p27, there may be higher expression in the crypt where it complexes with cdks (H. Smartt and L. Augenlicht, Albert Einstein Cancer Center; unpublished results). This raises the hypothesis that p27 in proliferating crypt cells, functions, at least in part, to restrain cycling cells from uncontrolled growth. Thus, it would then be clear why targeted inactivation of p27 is sufficient to initiate tumor formation (10).

Summary

The development of intestinal cancer, whether in well-defined, high-risk groups, in the general population or in mouse models is highly dependent upon dietary exposures. Although dietary factors influence the probability of tumor formation, they may exert only subtle affects on the trillions of cells that reside over a lifetime in the intestinal mucosa, only a very small number of which, even in groups at higher risk, will develop into neoplastic lesions. While pathways influenced by diet may produce phenotypically undetectable lesions at early stages of carcinogenesis, the techniques described herein provide unique mechanistic insights into the identification of diet-related gene expression patterns associated with higher risk of colorectal cancer. There is great potential to use these models to support the biologic plausibility for dietary prevention of colorectal cancer and for the identification of new or novel protective dietary factors.

FOOTNOTES

¹ Presented as part of the symposium "Nutritional ‘Omics’ Technologies for Elucidating the Roles of Bioactive Food Components in Colon Cancer Prevention" given at the 2005 Experimental Biology meeting on April 5, 2005, San Diego, CA. The symposium was sponsored by the American Society for Nutritional Sciences and in part by the Diet and Cancer and Dietary Bioactive Food Components Research Interest Sections. The proceedings are published as a supplement to The Journal of Nutrition. This supplement is the responsibility of the Guest Editors to whom the Editor of The Journal of Nutrition has delegated supervision of both technical conformity to the published regulations of The Journal of Nutrition and general oversight of the scientific merit of each article. The opinions expressed in this publication are those of the authors and are not attributable to the sponsors or the publisher, editor, or editorial board of The Journal of Nutrition. The guest editors for the supplement publication are Cindy D. Davis, National Cancer Institute, National Institutes of Health, and Norman Hord, Department of Food Science and Human Nutrition, Michigan State University.

³ Abbreviations used: cdki, cyclin dependent kinase inhibitor; NWD, new Western-style diet; WD, Western-style diet.

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