![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
3 Albert Einstein College of Medicine and Cancer Center, Montefiore Hospital/Oncology, Bronx, NY 10467 and 4 Strang Cancer Prevention Center, New York, NY 10021
* To whom correspondence should be addressed. E-mail: augen{at}aecom.yu.edu.
The profound effect of diet on modulating the development of human intestinal cancer can be effectively studied in the mouse. It has been demonstrated that a Western-style diet (WD)5 that mimics major risk factors for colon cancer in developed countries (high in fat, low in calcium and vitamin D) accelerates and increases tumor formation in mouse genetic models of cancer, including mice with targeted inactivation of Apc, Apc/p21WAF1/cip1, p27Kip1, and Apc/p27Kip1 (1–3). For example, although there is a gene dosage-dependent increase in tumor formation, and consequent decrease in life span, of Apc1638N+/– mice that are also p21+/+, p21+/–, or p21–/–, the Western diet exerts additive affects on tumor formation for each genotype (3). Further, the targeted inactivation of p27 in mice is sufficient to initiate tumor formation, but not if the animals are fed standard semipurified diet (2; our unpublished data). Tumors form in the large and small intestine of p27+/– or p27–/– mice if the animals are fed control AIN76A diet, and approximately double if animals of the same genotype are fed the WD diet. The p27+/– or p27–/– mice also develop intussusception, a pathology seen in patients with intestinal cancer but not yet reported in mouse genetic models, and the incidence of this pathology is markedly increased when the mice are fed the WD (4; our unpublished data). Elevated tumor development in these models is associated with a loss of proper intestinal cell maturation, especially a decrease in differentiated goblet cells (2,3). It has been demonstrated that loss of terminal goblet cell maturation in the intestine of mice with a targeted inactivation of the Muc2 gene is sufficient for tumor development throughout the intestinal tract (4,5) and that goblet cell maturation is more extensively perturbed, and tumor formation enhanced, in Muc2–/– mice that are also p21–/– (4).
These genetic models of intestinal cancer can therefore be highly useful in dissecting cellular and molecular pathways, and their interactions, that are involved in intestinal cancer. However, >90% of human colon cancer develops in the absence of an inherited mutation in tumor oncogenes or suppressor genes. Similarly, rodent models that utilize DMH and AOM have provided important insight into colon carcinogenesis and its chemo-/nutritional prevention, but these carcinogens are not related to initiators of human tumor development. We therefore developed a new mouse model that mimics the development of "sporadic" colon cancer, the tumors that account for at least 90% of the colon cancer in the United States. In this model, control C57 Bl/6 mice are fed a new western diet (NWD is the original WD, but with low levels of folate, choline, methionine, and fiber in addition to the low levels of calcium and vitamin D (6)) for 2 y, equivalent to about 80% of their normal life span. Although no tumors were seen at 12 mo, tumors appear by 18 mo and increase to 
1 tumor in 25% of the mice. This is similar to the development of single colon tumors found by colonoscopy in 25–50% of individuals after the age of 60 (again, 80% of the normal life span) in populations that consume a "higher-risk" diet. We therefore consider this a model of common sporadic colon cancer.
To gain insight into alterations that elevate risk for tumor development, expression profiling has been carried out utilizing RNA from isolated colonic epithelial cells of these control mice maintained on different diets for 3 mo, well before tumors begin to develop after 1 y. Shifts in expression of over 3000 sequences (of 27,000 screened) were detected in mice fed the NWD compared with those fed control AIN76A. Because prior work had demonstrated that increasing the low levels of calcium and vitamin D in the WD was effective in reversing the increase in tumor formation stimulated by the WD in several mouse genetic models (K. Yang, unpublished data), a third diet in which the NWD was supplemented with additional calcium and vitamin D was also investigated. In Bl/6 mice fed this supplemented diet, not only was tumor formation initiated by the NWD reversed, but the altered gene expression profile brought about by the NWD was also shifted back toward that seen in the mice fed AIN76A. Further investigation of the sequences whose level of expression closely tracked probabilities of tumor formation as well as calcium and vitamin D levels showed significant enrichment for genes in several functional groups: Wnt protein signaling, fat metabolism, redox pathways, and cytoskeleton.
Finally, methods for tracking profiles of gene expression that accompany the migration and maturation of cells along the crypt–villus axis in the mouse have been developed. These changes also fall into important functional groups (7). This database, along with other databases that have been published on altered profiles of gene expression in unique cell culture systems that undergo either cell lineage-specific differentiation (8–10) or perturbation of their normal gene expression programs under the influence of genetic mutations (11), is a valuable resource in dissection and interpretation of gene expression profiles that maintain normal mucosal homeostasis and the alterations that modulate probability of tumor development.
 |
FOOTNOTES |
|---|
2 Author disclosure: no relationships to disclose.
5 Abbreviations used: AOM, azoxymethane; DMH, dimethylhydrazine; NWD, new Western diet; WD, Western diet.
|
LITERATURE CITED |
|---|
 TOP LITERATURE CITED |
|---|
1. Yang K, Edelmann W, Fan K, Lau K, Leung D, Newmark H, Kucherlapati R, Lipkin M. Dietary modulation of carcinoma development in a mouse model for human familial polyposis. Cancer Res. 1998;58:5713–7.
2. Yang W. BancroftL, Nicholas C, Lozonschi I, Augenlicht LH. Targeted inactivation of p27kip1 is sufficient for large and small intestinal tumorigenesis in the mouse, which can be augmented by a western-style high-risk diet. Cancer Res. 2003;63:4990–6.
3. Yang WC, Mathew J, Velcich A, Edelmann W, Kucherlapati R, Lipkin M, Yang K, Augenlicht LH. Targeted inactivation of the p21 WAF1/cip1 gene enhances Apc initiated tumor formation and the tumor promoting activity of a Western-style high risk diet by altering cell maturation in the intestinal mucosa. Cancer Res. 2001;61:565–9.
4. Yang W, Velcich A, Lozonschi I, Liang J, Nicholas C, Zhuang M, Bancroft L, Augenicht LH. Inactivation of p21WAF1/cip1 enhances intestinal tumor formation in Muc2–/– mice. Am J Pathol. 2005;166:1239–46.
5. Velcich A, Yang WC, Heyer J, Fragale A, Nicholas C, Viani S, Kucherlapati R, Lipkin M, Yang K, Augenlicht L. Colorectal cancer in mice genetically deficient in the mucin Muc2. Science. 2002;295:1726–9.
6. Newmark HL, Yang K, Lipkin M, Kopelovich L, Liu Y, Fan K, Shinozaki HA. Western-style diet induces benign and malignant neoplasms in the colon of normal C57Bl/6 mice. Carcinogenesis. 2001;22:1871–5.
7. Mariadason J, Nicholas C, L'Italien K, Zhuang M, Smartt H, Heerdt B, Yang W, Corner G, Wilson A, et al. Gene expression profiling of intestinal epithelial cell maturation along the crypt-villus axis. Gastroenterology. 2005;128:1081–8.[Medline]
8. Mariadason JM, Arango D, Corner GA, Aranes MJ, Hotchkiss KA, Yang WC, Augenlicht LH. A gene expression profile that defines colon cell maturation in vitro. Cancer Res. 2002;62:4791–804.
9. Mariadason JM, Corner GA, Augenlicht LH. Genetic reprogramming in pathways of colonic cell maturation induced by short chain fatty acids: comparison with trichostatin A, sulidac, and curcumin and implications for chemoprevention of colon cancer. Cancer Res. 2000;60:4561–72.
10. Velcich A, Corner G, Paul D, Zhuang M, Mariadason JM, Laboisse C, Augenlicht L. Quantitative rather than qualitative differences in gene expression predominate in intestinal cell maturation along distinct cell lineages. Exp Cell Res. 2005;304:28–39.[Medline]
11. Klampfer L, Huang J, Corner G, Mariadason J, Arango D, Sasazuki T, Shirasawa S, Augenlicht L. Oncogenic k-ras inhibits the expression of IFN-responsive genes through inhibition of STAT1 and STAT2 expression. J Biol Chem. 2003;278:46278–87.
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
