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Animal models of colorectal cancer

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Abstract

Colorectal cancer is a heterogeneous disease that afflicts a large number of people in the USA. The use of animal models has the potential to increase our understanding of carcinogenesis, tumor biology, and the impact of specific molecular events on colon biology. In addition, animal models with features of specific human colorectal cancers can be used to test strategies for cancer prevention and treatment. In this review, we provide an overview of the mechanisms driving human cancer, we discuss the approaches one can take to model colon cancer in animals, and we describe a number of specific animal models that have been developed for the study of colon cancer. We believe that there are many valuable animal models to study various aspects of human colorectal cancer. However, opportunities for improving upon these models exist.

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References

  1. Rim, S. H., Seeff, L., Ahmed, F., et al. (2009). Colorectal cancer incidence in the United States, 1999–2004. Cancer, 115, 1967–1976.

    Article  PubMed  Google Scholar 

  2. American Cancer Society. (2011). Colorectal cancer facts & figures 2011–2013. Atlanta: American Cancer Society.

    Google Scholar 

  3. Fearon, E. R. (2011). Molecular genetics of colorectal cancer. Annual Review of Pathology, 6, 479–507.

    Article  PubMed  CAS  Google Scholar 

  4. Gervaz, P., Bucher, P., & Morel, P. (2004). Two colons-two cancers: paradigm shift and clinical implications. Journal of Surgical Oncology, 88, 261–266.

    Article  PubMed  Google Scholar 

  5. Fearon, E. R., & Vogelstein, B. (1990). A genetic model for colorectal tumorigenesis. Cell, 61, 759–767.

    Article  PubMed  CAS  Google Scholar 

  6. Wood, L. D., Parsons, D. W., Jones, S., Lin, J., Sjoblom, T., Leary, R. J., Shen, D., Boca, S. M., Barber, T., Ptak, J., Silliman, N., Szabo, S., Dezso, Z., Ustyanksky, V., Nikolskaya, T., Nikolsky, Y., Karchin, R., Wilson, P. A., Kaminker, J. S., Zhang, Z., Croshaw, R., Willis, J., Dawson, D., Shipitsin, M., Willson, J. K., Sukumar, S., Polyak, K., Park, B. H., Pethiyagoda, C. L., Pant, P. V., Ballinger, D. G., Sparks, A. B., Hartigan, J., Smith, D. R., Suh, E., Papadopoulos, N., Buckhaults, P., Markowitz, S. D., Parmigiani, G., Kinzler, K. W., Velculescu, V. E., & Vogelstein, B. (2007). The genomic landscapes of human breast and colorectal cancers. Science, 318, 1108–1113.

    Article  PubMed  CAS  Google Scholar 

  7. Leary, R. J., Lin, J. C., Cummins, J., Boca, S., Wood, L. D., Parsons, D. W., Jones, S., Sjöblom, T., Park, B. H., Parsons, R., Willis, J., Dawson, D., Willson, J. K. V., Nikolskaya, T., Nikolsky, Y., Kopelovich, L., Papadopoulos, N., Pennacchio, L. A., Wang, T. L., Markowitz, S. D., Parmigiani, G., Kinzler, K. W., Vogelstein, B., & Velculescu, V. E. (2008). Integrated analysis of homozygous deletions, focal amplifications, and sequence alterations in breast and colorectal cancers. Proceedings of the National Academy of Sciences, 105, 16224–16229.

    Article  CAS  Google Scholar 

  8. Knudson, A. G. (1971). Mutation and cancer: statistical study of retinoblastoma. Proceedings of the National Academy of Sciences of the United States of America, 68, 820–823.

    Article  PubMed  Google Scholar 

  9. Solomon, E., Voss, R., Hall, V., Bodmer, W. F., Jass, J. R., Jeffreys, A. J., Lucibello, F. C., Patel, I., & Rider, S. H. (1987). Chromosome 5 allele loss in human colorectal carcinomas. Nature, 328, 616–619.

    Article  PubMed  CAS  Google Scholar 

  10. Rubinfeld, B., Souza, B., Albert, I., Muller, O., Chamberlain, S. H., Masiarz, F. R., Munemitsu, S., & Polakis, P. (1993). Association of the APC gene product with beta-catenin. Science, 262, 1731–1734.

    Article  PubMed  CAS  Google Scholar 

  11. Munemitsu, S., Albert, I., Souza, B., Rubinfeld, B., & Polakis, P. (1995). Regulation of intracellular beta-catenin levels by the adenomatous polyposis coli (APC) tumor-suppressor protein. Proceedings of the National Academy of Sciences of the United States of America, 92, 3046–3050.

    Article  PubMed  CAS  Google Scholar 

  12. Sierra, J., Yoshida, T., Joazeiro, C. A., & Jones, K. A. (2006). The APC tumor suppressor counteracts beta-catenin activation and H3K4 methylation at Wnt target genes. Genes & Development, 20, 586–600.

    Article  CAS  Google Scholar 

  13. Henderson, B. R. (2000). Nuclear-cytoplasmic shuttling of APC regulates beta-catenin subcellular localization and turnover. Nature Cell Biology, 2, 653–660.

    Article  PubMed  CAS  Google Scholar 

  14. Porfiri, E., Rubinfeld, B., Albert, I., Hovanes, K., Waterman, M., & Polakis, P. (1997). Induction of a beta-catenin-LEF-1 complex by wnt-1 and transforming mutants of beta-catenin. Oncogene, 15, 2833–2839.

    Article  PubMed  CAS  Google Scholar 

  15. Senda, T., Iizuka-Kogo, A., Onouchi, T., & Shimomura, A. (2007). Adenomatous polyposis coli (APC) plays multiple roles in the intestinal and colorectal epithelia. Medical Molecular Morphology, 40, 68–81.

    Article  PubMed  Google Scholar 

  16. Phelps, R. A., Broadbent, T. J., Stafforini, D. M., & Jones, D. A. (2009). New perspectives on APC control of cell fate and proliferation in colorectal cancer. Cell Cycle, 8, 2549–2556.

    Article  PubMed  CAS  Google Scholar 

  17. Miyoshi, Y., Ando, H., Nagase, H., Nishisho, I., Horii, A., Miki, Y., Mori, T., Utsunomiya, J., Baba, S., & Petersen, G. (1992). Germ-line mutations of the APC gene in 53 familial adenomatous polyposis patients. Proceedings of the National Academy of Sciences of the United States of America, 89, 4452–4456.

    Article  PubMed  CAS  Google Scholar 

  18. Miyoshi, Y., Nagase, H., Ando, H., Horii, A., Ichii, S., Nakatsuru, S., Aoki, T., Miki, Y., Mori, T., & Nakamura, Y. (1992). Somatic mutations of the APC gene in colorectal tumors: mutation cluster region in the APC gene. Human Molecular Genetics, 1, 229–233.

    Article  PubMed  CAS  Google Scholar 

  19. Su, L. K., Vogelstein, B., & Kinzler, K. W. (1993). Association of the APC tumor suppressor protein with catenins. Science, 262, 1734–1737.

    Article  PubMed  CAS  Google Scholar 

  20. Spink, K. E., Polakis, P., & Weis, W. I. (2000). Structural basis of the axin-adenomatous polyposis coli interaction. The EMBO Journal, 19, 2270–2279.

    Article  PubMed  CAS  Google Scholar 

  21. Lamlum, H., Ilyas, M., Rowan, A., Clark, S., Johnson, V., Bell, J., Frayling, I., Efstathiou, J., Pack, K., Payne, S., Roylance, R., Gorman, P., Sheer, D., Neale, K., Phillips, R., Talbot, I., Bodmer, W., & Tomlinson, I. (1999). The type of somatic mutation at APC in familial adenomatous polyposis is determined by the site of the germline mutation: a new facet to Knudson's ‘two-hit’ hypothesis. Nature Medicine, 5, 1071–1075.

    Article  PubMed  CAS  Google Scholar 

  22. Albuquerque, C., Breukel, C., van der Luijt, R., Fidalgo, P., Lage, P., Slors, F. J. M., Leitúo, C. N., Fodde, R., & Smits, R. (2002). The “just-right” signaling model: APC somatic mutations are selected based on a specific level of activation of the beta-catenin signaling cascade. Human Molecular Genetics, 11, 1549–1560.

    Article  PubMed  CAS  Google Scholar 

  23. Rowan, A. J., Lamlum, H., Ilyas, M., Wheeler, J., Straub, J., Papadopoulou, A., Bicknell, D., Bodmer, W. F., & Tomlinson, I. P. (2000). APC mutations in sporadic colorectal tumors: a mutational “hotspot” and interdependence of the “two hits”. Proceedings of the National Academy of Sciences of the United States of America, 97, 3352–3357.

    Article  PubMed  CAS  Google Scholar 

  24. Crabtree, M., Sieber, O. M., Lipton, L., Hodgson, S. V., Lamlum, H., Thomas, H. J., Neale, K., Phillips, R. K., Heinimann, K., & Tomlinson, I. P. (2003). Refining the relation between ‘first hits’ and ‘second hits’ at the APC locus: the ‘loose fit’ model and evidence for differences in somatic mutation spectra among patients. Oncogene, 22, 4257–4265.

    Article  PubMed  CAS  Google Scholar 

  25. Vogelstein, B., Fearon, E. R., Hamilton, S. R., Kern, S. E., Preisinger, A. C., Leppert, M., Nakamura, Y., White, R., Smits, A. M., & Bos, J. L. (1988). Genetic alterations during colorectal-tumor development. The New England Journal of Medicine, 319, 525–532.

    Article  PubMed  CAS  Google Scholar 

  26. Castellano, E., & Downward, J. (2011). RAS interaction with PI3K: more than just another effector pathway. Genes Cancer, 2, 261–274.

    Article  PubMed  CAS  Google Scholar 

  27. Laurent-Puig, P., Cayre, A., Manceau, G., Buc, E., Bachet, J. B., Lecomte, T., Rougier, P., Lievre, A., Landi, B., Boige, V., Ducreux, M., Ychou, M., Bibeau, F., Bouche, O., Reid, J., Stone, S., & Penault-Llorca, F. (2009). Analysis of PTEN, BRAF, and EGFR status in determining benefit from cetuximab therapy in wild-type KRAS metastatic colon cancer. Journal of Clinical Oncology, 27, 5924–5930.

    Article  PubMed  CAS  Google Scholar 

  28. Lampropoulos, P., Zizi-Sermpetzoglou, A., Rizos, S., Kostakis, A., Nikiteas, N., & Papavassiliou, A. G. (2012). TGF-beta signalling in colon carcinogenesis. Cancer Letters, 314, 1–7.

    Article  PubMed  CAS  Google Scholar 

  29. Bellam, N., & Pasche, B. (2010). Tgf-beta signaling alterations and colon cancer. Cancer Treatment and Research, 155, 85–103.

    Article  PubMed  CAS  Google Scholar 

  30. Fearon, E. R., Cho, K. R., Nigro, J. M., Kern, S. E., Simons, J. W., Ruppert, J. M., Hamilton, S. R., Preisinger, A. C., Thomas, G., Kinzler, K. W., et al. (1990). Identification of a chromosome 18q gene that is altered in colorectal cancers. Science, 247, 49–56.

    Article  PubMed  CAS  Google Scholar 

  31. Mazelin, L., Bernet, A., Bonod-Bidaud, C., Pays, L., Arnaud, S., Gespach, C., Bredesen, D. E., Scoazec, J. Y., & Mehlen, P. (2004). Netrin-1 controls colorectal tumorigenesis by regulating apoptosis. Nature, 431, 80–84.

    Article  PubMed  CAS  Google Scholar 

  32. Castets, M., Broutier, L., Molin, Y., Brevet, M., Chazot, G., Gadot, N., Paquet, A., Mazelin, L., Jarrosson-Wuilleme, L., Scoazec, J.-Y., Bernet, A., & Mehlen, P. (2011). DCC constrains tumour progression via its dependence receptor activity. Nature, 482, 534–537.

    Article  PubMed  CAS  Google Scholar 

  33. Vousden, K. H., & Prives, C. (2009). Blinded by the light: the growing complexity of p53. Cell, 137, 413–431.

    Article  PubMed  CAS  Google Scholar 

  34. Geiersbach, K. B., & Samowitz, W. S. (2011). Microsatellite instability and colorectal cancer. Archives of Pathology & Laboratory Medicine, 135, 1269–1277.

    Article  CAS  Google Scholar 

  35. Isinger-Ekstrand, A., Therkildsen, C., Bernstein, I., & Nilbert, M. (2011). Deranged Wnt signaling is frequent in hereditary nonpolyposis colorectal cancer. Familial Cancer, 10, 239–243.

    Article  PubMed  CAS  Google Scholar 

  36. Miyaki, M., Iijima, T., Kimura, J., Yasuno, M., Mori, T., Hayashi, Y., Koike, M., Shitara, N., Iwama, T., & Kuroki, T. (1999). Frequent mutation of β-catenin and APC genes in primary colorectal tumors from patients with hereditary nonpolyposis colorectal cancer. Cancer Research, 59, 4506–4509.

    PubMed  CAS  Google Scholar 

  37. Kim, H., Jen, J., Vogelstein, B., & Hamilton, S. R. (1994). Clinical and pathological characteristics of sporadic colorectal carcinomas with DNA replication errors in microsatellite sequences. American Journal of Pathology, 145, 148–156.

    PubMed  CAS  Google Scholar 

  38. Cunningham, J. M., Christensen, E. R., Tester, D. J., Kim, C. Y., Roche, P. C., Burgart, L. J., & Thibodeau, S. N. (1998). Hypermethylation of the hMLH1 promoter in colon cancer with microsatellite instability. Cancer Research, 58, 3455–3460.

    PubMed  CAS  Google Scholar 

  39. Deng, G., Bell, I., Crawley, S., Gum, J., Terdiman, J. P., Allen, B. A., Truta, B., Sleisenger, M. H., & Kim, Y. S. (2004). BRAF mutation is frequently present in sporadic colorectal cancer with methylated hMLH1, but not in hereditary nonpolyposis colorectal cancer. Clinical Cancer Research, 10, 191–195.

    Article  PubMed  CAS  Google Scholar 

  40. Thorstensen, L., Lind, G. E., Lovig, T., Diep, C. B., Meling, G. I., Rognum, T. O., & Lothe, R. A. (2005). Genetic and epigenetic changes of components affecting the WNT pathway in colorectal carcinomas stratified by microsatellite instability. Neoplasia, 7, 98–108.

    Article  CAS  Google Scholar 

  41. Samowitz, W. S., Holden, J. A., Curtin, K., Edwards, S. L., Walker, A. R., Lin, H. A., Robertson, M. A., Nichols, M. F., Gruenthal, K. M., Lynch, B. J., Leppert, M. F., & Slattery, M. L. (2001). Inverse relationship between microsatellite instability and K-ras and p53 gene alterations in colon cancer. American Journal of Pathology, 158, 1517–1524.

    Article  PubMed  CAS  Google Scholar 

  42. Markowitz, S., Wang, J., Myeroff, L., Parsons, R., Sun, L., Lutterbaugh, J., Fan, R. S., Zborowska, E., Kinzler, K. W., Vogelstein, B., et al. (1995). Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability. Science, 268, 1336–1338.

    Article  PubMed  CAS  Google Scholar 

  43. Rampino, N., Yamamoto, H., Ionov, Y., Li, Y., Sawai, H., Reed, J. C., & Perucho, M. (1997). Somatic frameshift mutations in the BAX gene in colon cancers of the microsatellite mutator phenotype. Science, 275, 967–969.

    Article  PubMed  CAS  Google Scholar 

  44. Hawkins, N. J., Bariol, C., & Ward, R. L. (2002). The serrated neoplasia pathway. Pathology, 34, 548–555.

    PubMed  CAS  Google Scholar 

  45. Goldstein, N. S. (2006). Serrated pathway and APC (conventional)-type colorectal polyps: molecular-morphologic correlations, genetic pathways, and implications for classification. American Journal of Clinical Pathology, 125, 146–153.

    PubMed  CAS  Google Scholar 

  46. Church, E. M., Mehlhaff, C. J., & Patnaik, A. K. (1987). Colorectal adenocarcinoma in dogs: 78 cases (1973–1984). Journal of the American Veterinary Medical Association, 191, 727–730.

    PubMed  CAS  Google Scholar 

  47. McEntee, M. F., & Brenneman, K. A. (1999). Dysregulation of beta-catenin is common in canine sporadic colorectal tumors. Veterinary Pathology, 36, 228–236.

    Article  PubMed  CAS  Google Scholar 

  48. Valerius, K. D., Powers, B. E., McPherron, M. A., Hutchison, J. M., Mann, F. A., & Withrow, S. J. (1997). Adenomatous polyps and carcinoma in situ of the canine colon and rectum: 34 cases (1982–1994). Journal of the American Animal Hospital Association, 33, 156–160.

    PubMed  CAS  Google Scholar 

  49. Wolf, J. C., Ginn, P. E., Homer, B., Fox, L. E., & Kurzman, I. D. (1997). Immunohistochemical detection of p53 tumor suppressor gene protein in canine epithelial colorectal tumors. Veterinary Pathology, 34, 394–404.

    Article  PubMed  CAS  Google Scholar 

  50. Schaffer, E., & Schiefer, B. (1968). Incidence and types of canine rectal carcinomas. The Journal of Small Animal Practice, 9, 491–496.

    Article  Google Scholar 

  51. Cribb, A. E. (1988). Feline gastrointestinal adenocarcinoma: a review and retrospective study. Canadian Veterinary Journal, 29, 709–712.

    CAS  Google Scholar 

  52. Simpson, B. H. (1972). The geographic distribution of carcinomas of the small intestine in New Zealand sheep. New Zealand Veterinary Journal, 20, 24–28.

    Article  PubMed  CAS  Google Scholar 

  53. Munday, J. S., Brennan, M. M., Jaber, A. M., & Kiupel, M. (2006). Ovine intestinal adenocarcinomas: histologic and phenotypic comparison with human colon cancer. Comparative Medicine, 56, 136–141.

    PubMed  CAS  Google Scholar 

  54. Lushbaugh, C. C., Humason, G. L., Swartzendruber, D. C., Richter, C. B., & Gengozian, N. (1978). Spontaneous colonic adenocarcinoma in marmosets. Primates in Medicine, 10, 119–134.

    PubMed  CAS  Google Scholar 

  55. Cheverud, J. M., Tardif, S., Henke, M. A., & Clapp, N. K. (1993). Genetic epidemiology of colon cancer in the cotton-top tamarin (Saguinus oedipus). Human Biology, 65, 1005–1012.

    PubMed  CAS  Google Scholar 

  56. Wood, J. D., Peck, O. C., Tefend, K. S., Stonerook, M. J., Caniano, D. A., Mutabagani, K. H., Lhotak, S., & Sharma, H. M. (2000). Evidence that colitis is initiated by environmental stress and sustained by fecal factors in the cotton-top tamarin (Saguinus oedipus). Digestive Diseases and Sciences, 45, 385–393.

    Article  PubMed  CAS  Google Scholar 

  57. Mansfield, K. G., Lin, K. C., Xia, D., Newman, J. V., Schauer, D. B., MacKey, J., Lackner, A. A., & Carville, A. (2001). Enteropathogenic Escherichia coli and ulcerative colitis in cotton-top tamarins (Saguinus oedipus). Journal of Infectious Diseases, 184, 803–807.

    Article  PubMed  CAS  Google Scholar 

  58. Rowlatt, C., Franks, L. M., Sheriff, M. U., & Chesterman, F. C. (1969). Naturally occurring tumors and other lesions of the digestive tract in untreated C57BL mice. Journal of the National Cancer Institute, 43, 1353–1364.

    PubMed  CAS  Google Scholar 

  59. AIN. (1977). Report of the American Institute of Nutrition ad hoc committee on standards for nutritional studies. Journal of Nutrition, 107, 1340–1348.

    Google Scholar 

  60. Newmark, H. L., Yang, K., Kurihara, N., Fan, K., Augenlicht, L. H., & Lipkin, M. (2009). Western-style diet-induced colonic tumors and their modulation by calcium and vitamin D in C57Bl/6 mice: a preclinical model for human sporadic colon cancer. Carcinogenesis, 30, 88–92.

    Article  PubMed  CAS  Google Scholar 

  61. Magalhaes, B., Peleteiro, B., & Lunet, N. (2012). Dietary patterns and colorectal cancer: systematic review and meta-analysis. European Journal of Cancer Prevention, 21, 15–23.

    Article  PubMed  CAS  Google Scholar 

  62. Newmark, H. L., Lipkin, M., & Maheshwari, N. (1990). Colonic hyperplasia and hyperproliferation induced by a nutritional stress diet with four components of Western-style diet. Journal of the National Cancer Institute, 82, 491–496.

    Article  PubMed  CAS  Google Scholar 

  63. Richter, F., Newmark, H. L., Richter, A., Leung, D., & Lipkin, M. (1995). Inhibition of Western-diet induced hyperproliferation and hyperplasia in mouse colon by two sources of calcium. Carcinogenesis, 16, 2685–2689.

    Article  PubMed  CAS  Google Scholar 

  64. Risio, M., Lipkin, M., Newmark, H., Yang, K., Rossini, F. P., Steele, V. E., Boone, C. W., & Kelloff, G. J. (1996). Apoptosis, cell replication, and Western-style diet-induced tumorigenesis in mouse colon. Cancer Research, 56, 4910–4916.

    PubMed  CAS  Google Scholar 

  65. Newmark, H. L., Yang, K., Lipkin, M., Kopelovich, L., Liu, Y., Fan, K., & Shinozaki, H. (2001). A Western-style diet induces benign and malignant neoplasms in the colon of normal C57Bl/6 mice. Carcinogenesis, 22, 1871–1875.

    Article  PubMed  CAS  Google Scholar 

  66. Yang, K., Kurihara, N., Fan, K., Newmark, H., Rigas, B., Bancroft, L., Corner, G., Livote, E., Lesser, M., Edelmann, W., Velcich, A., Lipkin, M., & Augenlicht, L. (2008). Dietary induction of colonic tumors in a mouse model of sporadic colon cancer. Cancer Research, 68, 7803–7810.

    Article  PubMed  CAS  Google Scholar 

  67. Wang, D., Peregrina, K., Dhima, E., Lin, E. Y., Mariadason, J. M., & Augenlicht, L. H. (2011). Paneth cell marker expression in intestinal villi and colon crypts characterizes dietary induced risk for mouse sporadic intestinal cancer. Proceedings of the National Academy of Sciences of the United States of America, 108, 10277–2011.

    Google Scholar 

  68. Hunt, J. R., Hunt, C. D., Zito, C. A., Idso, J. P., & Johnson, L. K. (2008). Calcium requirements of growing rats based on bone mass, structure, or biomechanical strength are similar. Journal of Nutrition, 138, 1462–1468.

    PubMed  CAS  Google Scholar 

  69. Song, Y., & Fleet, J. C. (2007). Intestinal resistance to 1,25 dihydroxyvitamin d in mice heterozygous for the vitamin D receptor knockout allele. Endocrinology, 148, 1396–1402.

    Article  PubMed  CAS  Google Scholar 

  70. Turner, C. H., Hinckley, W. R., Wilson, M. E., Zhang, W., & Dunipace, A. J. (2001). Combined effects of diets with reduced calcium and phosphate and increased fluoride intake on vertebral bone strength and histology in rats. Calcified Tissue International, 69, 51–57.

    Article  PubMed  CAS  Google Scholar 

  71. Peterson, C. A., Eurell, J. C., & Erdman, J. W. (1995). Alterations in calcium intake on peak bone mass in the female rat. Journal of Bone and Mineral Research, 10, 81–95.

    Article  PubMed  CAS  Google Scholar 

  72. van Zeeland, A. A. (1996). Molecular dosimetry of chemical mutagens. Relationship between DNA adduct formation and genetic changes analyzed at the molecular level. Mutation Research, 353, 123–150.

    Article  PubMed  Google Scholar 

  73. Bissahoyo, A., Pearsall, R. S., Hanlon, K., Amann, V., Hicks, D., Godfrey, V. L., & Threadgill, D. W. (2005). Azoxymethane is a genetic background-dependent colorectal tumor initiator and promoter in mice: effects of dose, route, and diet. Toxicological Sciences, 88, 340–345.

    Article  PubMed  CAS  Google Scholar 

  74. Yamada, Y., Yoshimi, N., Hirose, Y., Kawabata, K., Matsunaga, K., Shimizu, M., Hara, A., & Mori, H. (2000). Frequent beta-catenin gene mutations and accumulations of the protein in the putative preneoplastic lesions lacking macroscopic aberrant crypt foci appearance, in rat colon carcinogenesis. Cancer Research, 60, 3323–3327.

    PubMed  CAS  Google Scholar 

  75. Perse, M., & Cerar, A. (2011). Morphological and molecular alterations in 1,2 dimethylhydrazine and azoxymethane induced colon carcinogenesis in rats. Journal of Biomedicine and Biotechnology, 2011, 473964.

    Article  PubMed  CAS  Google Scholar 

  76. Felton, J. S., Knize, M. G., Shen, N. H., Lewis, P. R., Andresen, B. D., Happe, J., & Hatch, F. T. (1986). The isolation and identification of a new mutagen from fried ground beef: 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Carcinogenesis, 7, 1081–1086.

    Article  PubMed  CAS  Google Scholar 

  77. Nakagama, H., Nakanishi, M., & Ochiai, M. (2005). Modeling human colon cancer in rodents using a food-borne carcinogen, PhIP. Cancer Science, 96, 627–636.

    Article  PubMed  CAS  Google Scholar 

  78. Tudek, B., Bird, R. P., & Bruce, W. R. (1989). Foci of aberrant crypts in the colons of mice and rats exposed to carcinogens associated with foods. Cancer Research, 49, 1236–1240.

    PubMed  CAS  Google Scholar 

  79. Esumi, H., Ohgaki, H., Kohzen, E., Takayama, S., & Sugimura, T. (1989). Induction of lymphoma in CDF1 mice by the food mutagen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine. Japanese Journal of Cancer Research, 80, 1176–1178.

    Article  PubMed  CAS  Google Scholar 

  80. Tanaka, T., Suzuki, R., Kohno, H., Sugie, S., Takahashi, M., & Wakabayashi, K. (2005). Colonic adenocarcinomas rapidly induced by the combined treatment with 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine and dextran sodium sulfate in male ICR mice possess beta-catenin gene mutations and increases immunoreactivity for beta-catenin, cyclooxygenase-2 and inducible nitric oxide synthase. Carcinogenesis, 26, 229–238.

    Article  PubMed  CAS  Google Scholar 

  81. Andreassen, A., Vikse, R., Mikalsen, A., Adamovic, T., Steffensen, I. L., Hjertholm, H., Levan, G., & Alexander, J. (2006). 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) induces genetic changes in murine intestinal tumours and cells with ApcMin mutation. Mutation Research, 604, 60–70.

    Article  PubMed  CAS  Google Scholar 

  82. Sinha, R., Chow, W. H., Kulldorff, M., DeNobile, J., Butler, J., Garcia-Closas, M., Weil, R., Hoover, R. N., & Rothman, N. (1999). Well-done, grilled red meat increases the risk of colorectal adenomas. Cancer Research, 59, 4320–4324.

    PubMed  CAS  Google Scholar 

  83. Sinha, R., & Rothman, N. (1999). Role of well-done, grilled red meat, heterocyclic amines (HCAs) in the etiology of human cancer. Cancer Letters, 143, 189–194.

    Article  PubMed  CAS  Google Scholar 

  84. Dashwood, R. H., Suzui, M., Nakagama, H., Sugimura, T., & Nagao, M. (1998). High frequency of beta-catenin (ctnnb1) mutations in the colon tumors induced by two heterocyclic amines in the F344 rat. Cancer Research, 58, 1127–1129.

    PubMed  CAS  Google Scholar 

  85. Tsukamoto, T., Tanaka, H., Fukami, H., Inoue, M., Takahashi, M., Wakabayashi, K., & Tatematsu, M. (2000). More frequent beta-catenin gene mutations in adenomas than in aberrant crypt foci or adenocarcinomas in the large intestines of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-treated rats. Japanese Journal of Cancer Research, 91, 729–796.

    Google Scholar 

  86. Fujiwara, K., Ochiai, M., Ohta, T., Ohki, M., Aburatani, H., Nagao, M., Sugimura, T., & Nakagama, H. (2004). Global gene expression analysis of rat colon cancers induced by a food-borne carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine. Carcinogenesis, 25, 1495–1505.

    Article  PubMed  CAS  Google Scholar 

  87. Ishiguro, Y., Ochiai, M., Sugimura, T., Nagao, M., & Nakagama, H. (1999). Strain differences of rats in the susceptibility to aberrant crypt foci formation by 2-amino-1-methyl-6-phenylimidazo- [4,5-b]pyridine: no implication of Apc and Pla2g2a genetic polymorphisms in differential susceptibility. Carcinogenesis, 20, 1063–1068.

    Article  PubMed  CAS  Google Scholar 

  88. Jobst, K. (1967). Teratogenous changes and tumors in rats following treatment with methylnitroso-urea (MNU). Neoplasma, 14, 435–436.

    PubMed  CAS  Google Scholar 

  89. Koestner, A. W., Ruecker, F. A., & Koestner, A. (1977). Morphology and pathogenesis of tumors of the thymus and stomach in Sprague–Dawley rats following intragastric administration of methyl nitrosourea (MNU). International Journal of Cancer, 20, 418–426.

    Article  CAS  Google Scholar 

  90. Maekawa, A., Onodera, H., Kanno, J., Furuta, K., Nagaoka, T., Todate, A., Matsushima, Y., Oh-hara, T., & Kawazoe, Y. (1988). Carcinogenicity and organ specificity of N-trimethylsilylmethyl-N-nitrosourea (TMS-MNU), N-neopentyl-N-nitrosourea (neoPNU), and N-methyl-N-nitrosourea (MNU) in rats. Journal of Cancer Research and Clinical Oncology, 114, 473–476.

    Article  PubMed  CAS  Google Scholar 

  91. Pollard, M., & Luckert, P. H. (1987). Autochthonous prostate adenocarcinomas in Lobund-Wistar rats: a model system. Prostate, 11, 219–227.

    Article  PubMed  CAS  Google Scholar 

  92. Tsubura, A., Lai, Y. C., Miki, H., Sasaki, T., Uehara, N., Yuri, T., & Yoshizawa, K. (2011). Review: animal models of N-methyl-N-nitrosourea-induced mammary cancer and retinal degeneration with special emphasis on therapeutic trials. In Vivo, 25, 11–22.

    PubMed  CAS  Google Scholar 

  93. Narisawa, T., Wong, C. Q., Maronpot, R. R., & Weisburger, J. H. (1976). Large bowel carcinogenesis in mice and rats by several intrarectal doses of methylnitrosourea and negative effect of nitrite plus methylurea. Cancer Research, 36, 505–510.

    PubMed  CAS  Google Scholar 

  94. Qin, X., Zarkovic, M., Nakatsuru, Y., Arai, M., Oda, H., & Ishikawa, T. (1994). DNA adduct formation and assessment of aberrant crypt foci in vivo in the rat colon mucosa after treatment with N-methyl-N-nitrosourea. Carcinogenesis, 15, 851–855.

    Article  PubMed  CAS  Google Scholar 

  95. Narisawa, T., & Weisburger, J. H. (1975). Colon cancer induction in mice by intrarectal instillation of N-methylnitosorurea (38498). Proceedings of the Society for Experimental Biology and Medicine, 148, 166–169.

    PubMed  CAS  Google Scholar 

  96. Sinkeldam, E. J., Kuper, C. F., Bosland, M. C., Hollanders, V. M., & Vedder, D. M. (1990). Interactive effects of dietary wheat bran and lard on N-methyl-N′-nitro-N-nitrosoguanidine-induced colon carcinogenesis in rats. Cancer Research, 50, 1092–1096.

    PubMed  CAS  Google Scholar 

  97. Endo, T., Ookawa, K., Tanaka, M., Nakaji, S., Tsuchida, S., & Sugawara, K. (2001). Differences in carcinogenesis by the length of carcinogen exposure period in rat colon. Digestive Diseases and Sciences, 46, 109–117.

    Article  PubMed  CAS  Google Scholar 

  98. Matusiak, D., Murillo, G., Carroll, R. E., Mehta, R. G., & Benya, R. V. (2005). Expression of vitamin D receptor and 25-hydroxyvitamin D3-1{alpha}-hydroxylase in normal and malignant human colon. Cancer Epidemiology, Biomarkers & Prevention, 14, 2370–2376.

    Article  CAS  Google Scholar 

  99. Shima, N., Swiger, R. R., & Heddle, J. A. (2000). Dietary restriction during murine development provides protection against MNU-induced mutations. Mutation Research, 470, 189–200.

    Article  PubMed  CAS  Google Scholar 

  100. Zhou, S. B., Wang, G. J., Zhu, Y., & Chen, B. Q. (2000). Effect of dietary fatty acids on colon tumorigenesis induced by methyl nitrosourea in rats. Biomedical and Environmental Sciences, 13, 105–116.

    PubMed  CAS  Google Scholar 

  101. Narisawa, T., Fukaura, Y., Terada, K., & Sekiguchi, H. (1999). Inhibitory effects of ursodeoxycholic acid on N-methylnitrosourea-induced colon carcinogenesis and colonic mucosal telomerase activity in F344 rats. Journal of Experimental & Clinical Cancer Research, 18, 259–266.

    CAS  Google Scholar 

  102. Jacoby, R. F., Alexander, R. J., Raicht, R. F., & Brasitus, T. A. (1992). K-ras oncogene mutations in rat colon tumors induced by N-methyl-N-nitrosourea. Carcinogenesis, 13, 45–49.

    Article  PubMed  CAS  Google Scholar 

  103. Bara, J., Forgue-Lafitte, M. E., Maurin, N., Flejou, J. F., & Zimber, A. (2003). Abnormal expression of gastric mucin in human and rat aberrant crypt foci during colon carcinogenesis. Tumour Biology, 24, 109–115.

    Article  PubMed  CAS  Google Scholar 

  104. Moser, A. R., Pitot, H. C., & Dove, W. F. (1990). A dominant mutation that predisposes to multiple intestinal neoplasia in the mouse. Science, 247, 322–324.

    Article  PubMed  CAS  Google Scholar 

  105. Su, L. K., Kinzler, K. W., Vogelstein, B., Preisinger, A. C., Moser, A. R., Luongo, C., Gould, K. A., & Dove, W. F. (1992). Multiple intestinal neoplasia caused by a mutation in the murine homolog of the APC gene. Science, 256, 668–670.

    Article  PubMed  CAS  Google Scholar 

  106. Luongo, C., Moser, A. R., Gledhill, S., & Dove, W. F. (1994). Loss of Apc(+) in intestinal adenomas from Min mice. Cancer Research, 54, 5947–5952.

    PubMed  CAS  Google Scholar 

  107. Yamada, Y., & Mori, H. (2007). Multistep carcinogenesis of the colon in Apc(Min/+) mouse. Cancer Science, 98, 6–10.

    Article  PubMed  CAS  Google Scholar 

  108. Mccart, A. E., Vickaryous, N. K., & Silver, A. (2008). Apc mice: models, modifiers and mutants. Pathology Research and Practice, 204, 479–490.

    Article  Google Scholar 

  109. Silverman, K. A., Koratkar, R., Siracusa, L. D., & Buchberg, A. M. (2002). Identification of the modifier of Min 2 (Mom2) locus, a new mutation that influences Apc-induced intestinal neoplasia. Genome Research, 12, 88–97.

    Article  PubMed  CAS  Google Scholar 

  110. Moser, A. R., Dove, W. F., Roth, K. A., & Gordon, J. I. (1992). The Min (multiple intestinal neoplasia) mutation: its effect on gut epithelial cell differentiation and interaction with a modifier system. The Journal of Cell Biology, 116, 1517–1526.

    Article  PubMed  CAS  Google Scholar 

  111. Jasperson, K. W., Tuohy, T. M., Neklason, D. W., & Burt, R. W. (2010). Hereditary and familial colon cancer. Gastroenterology, 138, 2044–2058.

    Article  PubMed  CAS  Google Scholar 

  112. Amos-Landgraf, J. M., Kwong, L. N., Kendziorski, C. M., Reichelderfer, M., Torrealba, J., Weichert, J., Haag, J. D., Chen, K. S., Waller, J. L., Gould, M. N., & Dove, W. F. (2007). A target-selected Apc-mutant rat kindred enhances the modeling of familial human colon cancer. Proceedings of the National Academy of Sciences of the United States of America, 104, 4036–4041.

    Article  PubMed  CAS  Google Scholar 

  113. Feil, R. (2007). Conditional somatic mutagenesis in the mouse using site-specific recombinases. Handbook of Experimental Pharmacology, 178, 3–28.

    Article  PubMed  CAS  Google Scholar 

  114. Birling, M. C., Gofflot, F., & Warot, X. (2009). Site-specific recombinases for manipulation of the mouse genome. Methods in Molecular Biology, 561, 245–263.

    Article  PubMed  CAS  Google Scholar 

  115. Feil, R., Wagner, J., Metzger, D., & Chambon, P. (1997). Regulation of Cre recombinase activity by mutated estrogen receptor ligand-binding domains. Biochemical and Biophysical Research Communications, 237, 752–757.

    Article  PubMed  CAS  Google Scholar 

  116. Jackson, E. L., Willis, N., Mercer, K., Bronson, R. T., Crowley, D., Montoya, R., Jacks, T., & Tuveson, D. A. (2001). Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras. Genes & Development, 15, 3243–3248.

    Article  CAS  Google Scholar 

  117. Madison, B. B., Dunbar, L., Qiao, X. T., Braunstein, K., Braunstein, E., & Gumucio, D. L. (2002). Cis elements of the villin gene control expression in restricted domains of the vertical (crypt) and horizontal (duodenum, cecum) axes of the intestine. Journal of Biological Chemistry, 277, 33275–33283.

    Article  PubMed  CAS  Google Scholar 

  118. El Marjou, F., Janssen, K. P., Chang, B. H., Li, M., Hindie, V., Chan, L., Louvard, D., Chambon, P., Metzger, D., & Robine, S. (2004). Tissue-specific and inducible Cre-mediated recombination in the gut epithelium. Genesis, 39, 186–193.

    Article  PubMed  CAS  Google Scholar 

  119. Saam, J. R., & Gordon, J. I. (1999). Inducible gene knockouts in the small intestinal and colonic epithelium. Journal of Biological Chemistry, 274, 38071–38082.

    Article  PubMed  CAS  Google Scholar 

  120. Simon, T. C., Roth, K. A., & Gordon, J. I. (1993). Use of transgenic mice to map cis-acting elements in the liver fatty acid-binding protein gene (Fabpl) that regulate its cell lineage-specific, differentiation-dependent, and spatial patterns of expression in the gut epithelium and in the liver acinus. The Journal of Biological Chemistry, 268, 18345–18358.

    PubMed  CAS  Google Scholar 

  121. Quaroni, A., Calnek, D., Quaroni, E., & Chandler, J. S. (1991). Keratin expression in rat intestinal crypt and villus cells. Analysis with a panel of monoclonal antibodies. The Journal of Biological Chemistry, 266, 11923–11931.

    PubMed  CAS  Google Scholar 

  122. Means, A. L., Xu, Y., Zhao, A., Ray, K. C., & Gu, G. (2008). A CK19(CreERT) knockin mouse line allows for conditional DNA recombination in epithelial cells in multiple endodermal organs. Genesis, 46, 318–323.

    Article  PubMed  CAS  Google Scholar 

  123. Barker, N., van Es, J. H., Kuipers, J., Kujala, P., van den Born, M., Cozijnsen, M., Haegebarth, A., Korving, J., Begthel, H., Peters, P. J., & Clevers, H. (2007). Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature, 449, 1003–1007.

    Article  PubMed  CAS  Google Scholar 

  124. Barker, N., & Clevers, H. (2010). Leucine-rich repeat-containing G-protein-coupled receptors as markers of adult stem cells. Gastroenterology, 138, 1681–1696.

    Article  PubMed  CAS  Google Scholar 

  125. Hinoi, T., Akyol, A., Theisen, B. K., Ferguson, D. O., Greenson, J. K., Williams, B. O., Cho, K. R., & Fearon, E. R. (2007). Mouse model of colonic adenoma-carcinoma progression based on somatic Apc inactivation. Cancer Research, 67, 9721–9730.

    Article  PubMed  CAS  Google Scholar 

  126. Akyol, A., Hinoi, T., Feng, Y., Bommer, G. T., Glaser, T. M., & Fearon, E. R. (2008). Generating somatic mosaicism with a Cre recombinase-microsatellite sequence transgene. Nature Methods, 5, 231–233.

    Article  PubMed  CAS  Google Scholar 

  127. Xue, Y., Johnson, R., DeSmet, M., Snyder, P. W., & Fleet, J. C. (2010). Generation of a transgenic mouse for colorectal cancer research with intestinal cre expression limited to the large intestine. Molecular Cancer Research, 8, 1095–1104.

    Article  PubMed  CAS  Google Scholar 

  128. Gum, J. R., Jr., Hicks, J. W., Crawley, S. C., Yang, S. C., Borowsky, A. D., Dahl, C. M., Kakar, S., Kim, D. H., Cardiff, R. D., & Kim, Y. S. (2004). Mice expressing SV40 T antigen directed by the intestinal trefoil factor promoter develop tumors resembling human small cell carcinoma of the colon. Molecular Cancer Research, 2, 504–513.

    PubMed  CAS  Google Scholar 

  129. Gum, J. R., Jr., Hicks, J. W., Gillespie, A. M., Rius, J. L., Treseler, P. A., Kogan, S. C., Carlson, E. J., Epstein, C. J., & Kim, Y. S. (2001). Mouse intestinal goblet cells expressing SV40 T antigen directed by the MUC2 mucin gene promoter undergo apoptosis upon migration to the villi. Cancer Research, 61, 3472–3479.

    PubMed  CAS  Google Scholar 

  130. Itoh, H., Inoue, N., & Podolsky, D. K. (1999). Goblet-cell-specific transcription of mouse intestinal trefoil factor gene results from collaboration of complex series of positive and negative regulatory elements. Biochemical Journal, 341(Pt 2), 461–472.

    Article  PubMed  CAS  Google Scholar 

  131. Beuling, E., Baffour-Awuah, N. Y., Stapleton, K. A., Aronson, B. E., Noah, T. K., Shroyer, N. F., Duncan, S. A., Fleet, J. C., & Krasinski, S. D. (2011). GATA factors regulate proliferation, differentiation, and gene expression in small intestine of mature mice. Gastroenterology, 140, 1219–1229.

    Article  PubMed  CAS  Google Scholar 

  132. Kistner, A., Gossen, M., Zimmermann, F., Jerecic, J., Ullmer, C., Lubbert, H., & Bujard, H. (1996). Doxycycline-mediated quantitative and tissue-specific control of gene expression in transgenic mice. Proceedings of the National Academy of Sciences of the United States of America, 93, 10933–10938.

    Article  PubMed  CAS  Google Scholar 

  133. Furth, P. A., St, O. L., Boger, H., Gruss, P., Gossen, M., Kistner, A., Bujard, H., & Hennighausen, L. (1994). Temporal control of gene expression in transgenic mice by a tetracycline-responsive promoter. Proceedings of the National Academy of Sciences of the United States of America, 91, 9302–9306.

    Article  PubMed  CAS  Google Scholar 

  134. St-Onge, L., Furth, P. A., & Gruss, P. (1996). Temporal control of the Cre recombinase in transgenic mice by a tetracycline responsive promoter. Nucleic Acids Research, 24, 3875–3877.

    Article  PubMed  CAS  Google Scholar 

  135. Ireland, H., Kemp, R., Houghton, C., Howard, L., Clarke, A. R., Sansom, O. J., & Winton, D. J. (2004). Inducible Cre-mediated control of gene expression in the murine gastrointestinal tract: effect of loss of beta-catenin. Gastroenterology, 126, 1236–1246.

    Article  PubMed  CAS  Google Scholar 

  136. Barker, N., Ridgway, R. A., van Es, J. H., van de Wetering, M., Begthel, H., van den Born, M., Danenberg, E., Clarke, A. R., Sansom, O. J., & Clevers, H. (2009). Crypt stem cells as the cells-of-origin of intestinal cancer. Nature, 457, 608–611.

    Article  PubMed  CAS  Google Scholar 

  137. Ireland, H., Houghton, C., Howard, L., & Winton, D. J. (2005). Cellular inheritance of a Cre-activated reporter gene to determine Paneth cell longevity in the murine small intestine. Developmental Dynamics, 233, 1332–1336.

    Article  PubMed  CAS  Google Scholar 

  138. Hung, K. E., Maricevich, M. A., Richard, L. G., Chen, W. Y., Richardson, M. P., Kunin, A., Bronson, R. T., Mahmood, U., & Kucherlapati, R. (2010). Development of a mouse model for sporadic and metastatic colon tumors and its use in assessing drug treatment. Proceedings of the National Academy of Sciences of the United States of America, 107, 1565–1570.

    Article  PubMed  CAS  Google Scholar 

  139. Shibata, H., Toyama, K., Shioya, H., Ito, M., Hirota, M., Hasegawa, S., Matsumoto, H., Takano, H., Akiyama, T., Toyoshima, K., Kanamaru, R., Kanegae, Y., Saito, I., Nakamura, Y., Shiba, K., & Noda, T. (1997). Rapid colorectal adenoma formation initiated by conditional targeting of the Apc gene. Science, 278, 120–123.

    Article  PubMed  CAS  Google Scholar 

  140. Poulogiannis, G., Frayling, I. M., & Arends, M. J. (2010). DNA mismatch repair deficiency in sporadic colorectal cancer and Lynch syndrome. Histopathology, 56, 167–179.

    Article  PubMed  Google Scholar 

  141. Oshima, M., Oshima, H., Kitagawa, K., Kobayashi, M., Itakura, C., & Taketo, M. (1995). Loss of Apc heterozygosity and abnormal tissue building in nascent intestinal polyps in mice carrying a truncated Apc gene. Proceedings of the National Academy of Sciences of the United States of America, 92, 4482–4486.

    Article  PubMed  CAS  Google Scholar 

  142. Sasai, H., Masaki, M., & Wakitani, K. (2000). Suppression of polypogenesis in a new mouse strain with a truncated Apc(Delta474) by a novel COX-2 inhibitor, JTE-522. Carcinogenesis, 21, 953–958.

    Article  PubMed  CAS  Google Scholar 

  143. Pollard, P., Deheragoda, M., Segditsas, S., Lewis, A., Rowan, A., Howarth, K., Willis, L., Nye, E., McCart, A., Mandir, N., Silver, A., Goodlad, R., Stamp, G., Cockman, M., East, P., Spencer-Dene, B., Poulsom, R., Wright, N., & Tomlinson, I. (2009). The Apc 1322T mouse develops severe polyposis associated with submaximal nuclear beta-catenin expression. Gastroenterology, 136, 2204–2213.

    Article  PubMed  CAS  Google Scholar 

  144. Fodde, R., Edelmann, W., Yang, K., van Leeuwen, C., Carlson, C., Renault, B., Breukel, C., Alt, E., Lipkin, M., & Khan, P. M. (1994). A targeted chain-termination mutation in the mouse Apc gene results in multiple intestinal tumors. Proceedings of the National Academy of Sciences of the United States of America, 91, 8969–8973.

    Article  PubMed  CAS  Google Scholar 

  145. Smits, R., Kielman, M. F., Breukel, C., Zurcher, C., Neufeld, K., Jagmohan-Changur, S., Hofland, N., van Dijk, J., White, R., Edelmann, W., Kucherlapati, R., Khan, P. M., & Fodde, R. (1999). Apc1638T: a mouse model delineating critical domains of the adenomatous polyposis coli protein involved in tumorigenesis and development. Genes & Development, 13, 1309–1321.

    Article  CAS  Google Scholar 

  146. Lewis, A., Davis, H., Deheragoda, M., Pollard, P., Nye, E., Jeffery, R., Segditsas, S., East, P., Poulsom, R., Stamp, G., Wright, N., & Tomlinson, I. (2012). The C-terminus of Apc does not influence intestinal adenoma development or progression. The Journal of Pathology, 226, 73–83.

    Article  PubMed  CAS  Google Scholar 

  147. Gaspar, C., Franken, P., Molenaar, L., Breukel, C., van der Valk, M., Smits, R., & Fodde, R. (2009). A targeted constitutive mutation in the APC tumor suppressor gene underlies mammary but not intestinal tumorigenesis. PLoS Genet, 5, e1000547.

    Article  PubMed  CAS  Google Scholar 

  148. Ito, M., Miura, S., & Noda, T. (1995). Mouse model for familial adenomatous polyposis coli and APC gene. Tanpakushitsu Kakusan Koso, 40, 2035–2044.

    PubMed  CAS  Google Scholar 

  149. Quesada, C. F., Kimata, H., Mori, M., Nishimura, M., Tsuneyoshi, T., & Baba, S. (1998). Piroxicam and acarbose as chemopreventive agents for spontaneous intestinal adenomas in APC gene 1309 knockout mice. Japanese Journal of Cancer Research, 89, 392–396.

    Article  PubMed  CAS  Google Scholar 

  150. Colnot, S., Niwa-Kawakita, M., Hamard, G., Godard, C., Le Plenier, S., Houbron, C., Romagnolo, N., Berrebi, D., Giovannini, M., & Perret, C. (2004). Colorectal cancers in a new mouse model of familial adenomatous polyposis: influence of genetic and environmental modifiers. Laboratory Investigation, 84, 1619–1630.

    Article  PubMed  CAS  Google Scholar 

  151. Kuraguchi, M., Wang, X. P., Bronson, R. T., Rothenberg, R., Ohene-Baah, N. Y., Lund, J. J., Kucherlapati, M., Maas, R. L., & Kucherlapati, R. (2006). Adenomatous polyposis coli (APC) is required for normal development of skin and thymus. PLoS Genetics, 2, 1362–1374.

    Article  CAS  Google Scholar 

  152. Sansom, O. J., Reed, K. R., Hayes, A. J., Ireland, H., Brinkmann, H., Newton, I. P., Batlle, E., Simon-Assmann, P., Clevers, H., Nathke, I. S., Clarke, A. R., & Winton, D. J. (2004). Loss of Apc in vivo immediately perturbs Wnt signaling, differentiation, and migration. Genes & Development, 18, 1385–1390.

    Article  CAS  Google Scholar 

  153. Robanus-Maandag, E. C., Koelink, P. J., Breukel, C., Salvatori, D. C., Jagmohan-Changur, S. C., Bosch, C. A., Verspaget, H. W., Devilee, P., Fodde, R., & Smits, R. (2010). A new conditional Apc-mutant mouse model for colorectal cancer. Carcinogenesis, 31, 946–952.

    Article  PubMed  CAS  Google Scholar 

  154. Zeineldin, M., Cunningham, J., McGuinness, W., Alltizer, P., Cowley, B., Blanchat, B., Xu, W., Pinson, D., & Neufeld, K. L. (2012). A knock-in mouse model reveals roles for nuclear Apc in cell proliferation, Wnt signal inhibition and tumor suppression. Oncogene, 31, 2423–2437.

    Article  PubMed  CAS  Google Scholar 

  155. Svetlanov, A., & Cohen, P. E. (2004). Mismatch repair proteins, meiosis, and mice: understanding the complexities of mammalian meiosis. Experimental Cell Research, 296, 71–79.

    Article  PubMed  CAS  Google Scholar 

  156. Edelmann, W., Yang, F., Kuraguchi, M., Heyer, J., Lia, M., Kneitz, B., Fan, K. H., Brown, A. M. C., Lipkin, M., & Kucherlapati, R. (1999). Tumorigenesis in Mlh1 and Mlh1/Apc1638N mutant mice. Cancer Research, 59, 1301–1307.

    PubMed  CAS  Google Scholar 

  157. Reitmair, A. H., Redston, M., Cai, J. C., Chuang, T. C., Bjerknes, M., Cheng, H., Hay, K., Gallinger, S., Bapat, B., & Mak, T. W. (1996). Spontaneous intestinal carcinomas and skin neoplasms in Msh2-deficient mice. Cancer Research, 56, 3842–3849.

    PubMed  CAS  Google Scholar 

  158. Reitmair, A. H., Cai, J. C., Bjerknes, M., Redston, M., Cheng, H., Pind, M. T., Hay, K., Mitri, A., Bapat, B. V., Mak, T. W., & Gallinger, S. (1996). MSH2 deficiency contributes to accelerated APC-mediated intestinal tumorigenesis. Cancer Research, 56, 2922–2926.

    PubMed  CAS  Google Scholar 

  159. Luo, F., Brooks, D. G., Ye, H., Hamoudi, R., Poulogiannis, G., Patek, C. E., Winton, D. J., & Arends, M. J. (2007). Conditional expression of mutated K-ras accelerates intestinal tumorigenesis in Msh2-deficient mice. Oncogene, 26, 4415–4427.

    Article  PubMed  CAS  Google Scholar 

  160. Kucherlapati, M. H., Lee, K., Nguyen, A. A., Clark, A. B., Hou, H., Jr., Rosulek, A., Li, H., Yang, K., Fan, K., Lipkin, M., Bronson, R. T., Jelicks, L., Kunkel, T. A., Kucherlapati, R., & Edelmann, W. (2010). An Msh2 conditional knockout mouse for studying intestinal cancer and testing anticancer agents. Gastroenterology, 138, 993–1002.

    Article  PubMed  Google Scholar 

  161. Boland, C. R., & Goel, A. (2010). Microsatellite instability in colorectal cancer. Gastroenterology, 138, 2073–2087.

    Article  PubMed  CAS  Google Scholar 

  162. Wind, N. D., Dekker, M., Claij, N., Jansen, L., Klink, Y. V., Radman, M., Riggins, G., Valk, M. V. D., van’t Wout, K., & Riele, H. T. (1999). HNPCC-like cancer predisposition in mice through simultaneous loss of Msh3 and Msh6 mismatch-repair protein functions. Nature Genetics, 23, 359–362.

    Article  PubMed  Google Scholar 

  163. Chen, P. C., Dudley, S., Hagen, W., Dizon, D., Paxton, L., Reichow, D., Yoon, S. R., Yang, K., Arnheim, N., Liskay, R. M., & Lipkin, S. M. (2005). Contributions by MutL homologues Mlh3 and Pms2 to DNA mismatch repair and tumor suppression in the mouse. Cancer Research, 65, 8662–8670.

    Article  PubMed  CAS  Google Scholar 

  164. Chen, P. C., Kuraguchi, M., Velasquez, J., Wang, Y., Yang, K., Edwards, R., Gillen, D., Edelmann, W., Kucherlapati, R., & Lipkin, S. M. (2008). Novel roles for MLH3 deficiency and TLE6-like amplification in DNA mismatch repair-deficient gastrointestinal tumorigenesis and progression. PLoS Genet, 4, e1000092.

    Article  PubMed  CAS  Google Scholar 

  165. Harada, N., Tamai, Y., Ishikawa, T., Sauer, B., Takaku, K., Oshima, M., & Taketo, M. M. (1999). Intestinal polyposis in mice with a dominant stable mutation of the beta-catenin gene. EMBO Journal, 18, 5931–5942.

    Article  PubMed  CAS  Google Scholar 

  166. Tuveson, D. A., Shaw, A. T., Willis, N. A., Silver, D. P., Jackson, E. L., Chang, S., Mercer, K. L., Grochow, R., Hock, H., Crowley, D., Hingorani, S. R., Zaks, T., King, C., Jacobetz, M. A., Wang, L., Bronson, R. T., Orkin, S. H., DePinho, R. A., & Jacks, T. (2004). Endogenous oncogenic K-ras(G12D) stimulates proliferation and widespread neoplastic and developmental defects. Cancer Cell, 5, 375–387.

    Article  PubMed  CAS  Google Scholar 

  167. Haigis, K. M., Kendall, K. R., Wang, Y., Cheung, A., Haigis, M. C., Glickman, J. N., Niwa-Kawakita, M., Sweet-Cordero, A., Sebolt-Leopold, J., Shannon, K. M., Settleman, J., Giovannini, M., & Jacks, T. (2008). Differential effects of oncogenic K-Ras and N-Ras on proliferation, differentiation and tumor progression in the colon. Nature Genetics, 40, 600–608.

    Article  PubMed  CAS  Google Scholar 

  168. Calcagno, S. R., Li, S., Colon, M., Kreinest, P. A., Thompson, E. A., Fields, A. P., & Murray, N. R. (2008). Oncogenic K-ras promotes early carcinogenesis in the mouse proximal colon. International Journal of Cancer, 122, 2462–2470.

    Article  CAS  Google Scholar 

  169. Feng, Y., Bommer, G. T., Zhao, J., Green, M., Sands, E., Zhai, Y., Brown, K., Burberry, A., Cho, K. R., & Fearon, E. R. (2011). Mutant KRAS promotes hyperplasia and alters differentiation in the colon epithelium but does not expand the presumptive stem cell pool. Gastroenterology, 141, 1003–1013.

    Article  PubMed  CAS  Google Scholar 

  170. Luo, F., Brooks, D. G., Ye, H., Hamoudi, R., Poulogiannis, G., Patek, C. E., Winton, D. J., & Arends, M. J. (2009). Mutated K-ras(Asp12) promotes tumourigenesis in Apc(Min) mice more in the large than the small intestines, with synergistic effects between K-ras and Wnt pathways. International Journal of Experimental Pathology, 90, 558–574.

    Article  PubMed  CAS  Google Scholar 

  171. Trobridge, P., Knoblaugh, S., Washington, M. K., Munoz, N. M., Tsuchiya, K. D., Rojas, A., Song, X., Ulrich, C. M., Sasazuki, T., Shirasawa, S., & Grady, W. M. (2009). TGF-beta receptor inactivation and mutant Kras induce intestinal neoplasms in mice via a beta-catenin-independent pathway. Gastroenterology, 136, 1680–1688.

    Article  PubMed  CAS  Google Scholar 

  172. Luo, F., Poulogiannis, G., Ye, H., Hamoudi, R., Zhang, W., Dong, G., & Arends, M. J. (2011). Mutant K-ras promotes carcinogen-induced murine colorectal tumourigenesis, but does not alter tumour chromosome stability. The Journal of Pathology, 223, 390–399.

    Article  PubMed  CAS  Google Scholar 

  173. Harvey, M., McArthur, M. J., Montgomery, C. A., Jr., Bradley, A., & Donehower, L. A. (1993). Genetic background alters the spectrum of tumors that develop in p53-deficient mice. The FASEB Journal, 7, 938–943.

    CAS  Google Scholar 

  174. Harvey, M., McArthur, M. J., Montgomery, C. A., Jr., Butel, J. S., Bradley, A., & Donehower, L. A. (1993). Spontaneous and carcinogen-induced tumorigenesis in p53-deficient mice. Nature Genetics, 5, 225–229.

    Article  PubMed  CAS  Google Scholar 

  175. Hu, Y., Le Leu, R. K., & Young, G. P. (2005). Absence of acute apoptotic response to genotoxic carcinogens in p53-deficient mice is associated with increased susceptibility to azoxymethane-induced colon tumours. International Journal of Cancer, 115, 561–567.

    Article  CAS  Google Scholar 

  176. Hu, Y., Le Leu, R. K., Belobrajdic, D., & Young, G. P. (2008). The potential of sphingomyelin as a chemopreventive agent in AOM-induced colon cancer model: wild-type and p53+/− mice. Molecular Nutrition & Food Research, 52, 558–566.

    Article  CAS  Google Scholar 

  177. Mladenova, D., Daniel, J. J., Dahlstrom, J. E., Bean, E., Gupta, R., Pickford, R., Currey, N., Musgrove, E. A., & Kohonen-Corish, M. R. (2011). The NSAID sulindac is chemopreventive in the mouse distal colon but carcinogenic in the proximal colon. Gut, 60, 350–360.

    Article  PubMed  CAS  Google Scholar 

  178. Sakai, H., Tsukamoto, T., Yamamoto, M., Shirai, N., Iidaka, T., Hirata, A., Yanai, T., Masegi, T., Donehower, L. A., & Tatematsu, M. (2003). High susceptibility of nullizygous p53 knockout mice to colorectal tumor induction by 1,2-dimethylhydrazine. Journal of Cancer Research and Clinical Oncology, 129, 335–340.

    Article  PubMed  CAS  Google Scholar 

  179. Fujii, S., Fujimori, T., Kawamata, H., Takeda, J., Kitajima, K., Omotehara, F., Kaihara, T., Kusaka, T., Ichikawa, K., Ohkura, Y., Ono, Y., Imura, J., Yamaoka, S., Sakamoto, C., Ueda, Y., & Chiba, T. (2004). Development of colonic neoplasia in p53 deficient mice with experimental colitis induced by dextran sulphate sodium. Gut, 53, 710–716.

    Article  PubMed  CAS  Google Scholar 

  180. Reed, K. R., Meniel, V. S., Marsh, V., Cole, A., Sansom, O. J., & Clarke, A. R. (2008). A limited role for p53 in modulating the immediate phenotype of Apc loss in the intestine. BMC Cancer, 8, 162.

    Article  PubMed  CAS  Google Scholar 

  181. Valentin-Vega, Y. A., Okano, H., & Lozano, G. (2008). The intestinal epithelium compensates for p53-mediated cell death and guarantees organismal survival. Cell Death and Differentiation, 15, 1772–1781.

    Article  PubMed  CAS  Google Scholar 

  182. Yang, W. C., Mathew, J., Velcich, A., Edelmann, W., Kucherlapati, R., Lipkin, M., Yang, K., & Augenlicht, L. H. (2001). 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 mucosal. Cancer Research, 61, 565–569.

    PubMed  CAS  Google Scholar 

  183. Yang, W., Bancroft, L., Nicholas, C., Lozonschi, I., & Augenlicht, L. H. (2003). 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 Research, 63, 4990–4996.

    PubMed  CAS  Google Scholar 

  184. Philipp-Staheli, J., Kim, K. H., Payne, S. R., Gurley, K. E., Liggitt, D., Longton, G., & Kemp, C. J. (2002). Pathway-specific tumor suppression. Reduction of p27 accelerates gastrointestinal tumorigenesis in Apc mutant mice, but not in Smad3 mutant mice. Cancer Cell, 1, 355–368.

    Article  PubMed  Google Scholar 

  185. Shao, J., Washington, M. K., Saxena, R., & Sheng, H. (2007). Heterozygous disruption of the PTEN promotes intestinal neoplasia in APCmin/+ mouse: roles of osteopontin. Carcinogenesis, 28, 2476–2483.

    Article  PubMed  CAS  Google Scholar 

  186. Marsh, V., Winton, D. J., Williams, G. T., Dubois, N., Trumpp, A., Sansom, O. J., & Clarke, A. R. (2008). Epithelial Pten is dispensable for intestinal homeostasis but suppresses adenoma development and progression after Apc mutation. Nature Genetics, 40, 1436–1444.

    Article  PubMed  CAS  Google Scholar 

  187. Gendler, S. J., & Spicer, A. P. (1995). Epithelial mucin genes. Annual Review of Physiology, 57, 607–634.

    Article  PubMed  CAS  Google Scholar 

  188. Johansson, M. E., Phillipson, M., Petersson, J., Velcich, A., Holm, L., & Hansson, G. C. (2008). The inner of the two Muc2 mucin-dependent mucus layers in colon is devoid of bacteria. Proceedings of the National Academy of Sciences of the United States of America, 105, 15064–15069.

    Article  PubMed  CAS  Google Scholar 

  189. Velcich, A., Yang, W., Heyer, J., Fragale, A., Nicholas, C., Viani, S., Kucherlapati, R., Lipkin, M., Yang, K., & Augenlicht, L. (2002). Colorectal cancer in mice genetically deficient in the mucin Muc2. Science, 295, 1726–1729.

    Article  PubMed  CAS  Google Scholar 

  190. Yang, K., Popova, N. V., Yang, W. C., Lozonschi, I., Tadesse, S., Kent, S., Bancroft, L., Matise, I., Cormier, R. T., Scherer, S. J., Edelmann, W., Lipkin, M., Augenlicht, L., & Velcich, A. (2008). Interaction of Muc2 and Apc on Wnt signaling and in intestinal tumorigenesis: potential role of chronic inflammation. Cancer Research, 68, 7313–7322.

    Article  PubMed  CAS  Google Scholar 

  191. Koepp, D. M., Schaefer, L. K., Ye, X., Keyomarsi, K., Chu, C., Harper, J. W., & Elledge, S. J. (2001). Phosphorylation-dependent ubiquitination of cyclin E by the SCFFbw7 ubiquitin ligase. Science, 294, 173–177.

    Article  PubMed  CAS  Google Scholar 

  192. Welcker, M., Orian, A., Jin, J., Grim, J. E., Harper, J. W., Eisenman, R. N., & Clurman, B. E. (2004). The Fbw7 tumor suppressor regulates glycogen synthase kinase 3 phosphorylation-dependent c-Myc protein degradation. Proceedings of the National Academy of Sciences of the United States of America, 101, 9085–9090.

    Article  PubMed  CAS  Google Scholar 

  193. Babaei-Jadidi, R., Li, N., Saadeddin, A., Spencer-Dene, B., Jandke, A., Muhammad, B., Ibrahim, E. E., Muraleedharan, R., Abuzinadah, M., Davis, H., Lewis, A., Watson, S., Behrens, A., Tomlinson, I., & Nateri, A. S. (2011). FBXW7 influences murine intestinal homeostasis and cancer, targeting Notch, Jun, and DEK for degradation. The Journal of Experimental Medicine, 208, 295–312.

    Article  PubMed  CAS  Google Scholar 

  194. Starr, T. K., Allaei, R., Silverstein, K. A., Staggs, R. A., Sarver, A. L., Bergemann, T. L., Gupta, M., O’Sullivan, M. G., Matise, I., Dupuy, A. J., Collier, L. S., Powers, S., Oberg, A. L., Asmann, Y. W., Thibodeau, S. N., Tessarollo, L., Copeland, N. G., Jenkins, N. A., Cormier, R. T., & Largaespada, D. A. (2009). A transposon-based genetic screen in mice identifies genes altered in colorectal cancer. Science, 323, 1747–1750.

    Article  PubMed  CAS  Google Scholar 

  195. Zhu, Y., Richardson, J. A., Parada, L. F., & Graff, J. M. (1998). Smad3 mutant mice develop metastatic colorectal cancer. Cell, 94, 703–714.

    Article  PubMed  CAS  Google Scholar 

  196. Maggio-Price, L., Treuting, P., Zeng, W., Tsang, M., Bielefeldt-Ohmann, H., & Iritani, B. M. (2006). Helicobacter infection is required for inflammation and colon cancer in SMAD3-deficient mice. Cancer Research, 66, 828–838.

    Article  PubMed  CAS  Google Scholar 

  197. Chytil, A., Magnuson, M. A., Wright, C. V., & Moses, H. L. (2002). Conditional inactivation of the TGF-beta type II receptor using Cre: Lox. Genesis, 32, 73–75.

    Article  PubMed  CAS  Google Scholar 

  198. Reitmair, A. H., Schmits, R., Ewel, A., Bapat, B., Redston, M., Mitri, A., Waterhouse, P., Mittrucker, H. W., Wakeham, A., & Liu, B. (1995). MSH2 deficient mice are viable and susceptible to lymphoid tumours. Nature Genetics, 11, 64–70.

    Article  PubMed  CAS  Google Scholar 

  199. Engle, S. J., Ormsby, I., Pawlowski, S., Boivin, G. P., Croft, J., Balish, E., & Doetschman, T. (2002). Elimination of colon cancer in germ-free transforming growth factor beta 1-deficient mice. Cancer Research, 62, 6362–6366.

    PubMed  CAS  Google Scholar 

  200. Takahashi, M., & Wakabayashi, K. (2004). Gene mutations and altered gene expression in azoxymethane-induced colon carcinogenesis in rodents. Cancer Science, 95, 475–480.

    Article  PubMed  CAS  Google Scholar 

  201. Yang, X., Young, L. H., & Voigt, J. M. (1998). Expression of a vitamin D-regulated gene (VDUP-1) in untreated- and MNU-treated rat mammary tissue. Breast Cancer Research and Treatment, 48, 33–44.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This study was supported by NIH award CA165240 to J.C.F.

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Johnson, R.L., Fleet, J.C. Animal models of colorectal cancer. Cancer Metastasis Rev 32, 39–61 (2013). https://doi.org/10.1007/s10555-012-9404-6

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