APC Proteins pp 85-106 | Cite as

APC and Its Modifiers in Colon Cancer

  • Lawrence N. Kwong
  • William F. Dove
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 656)


Colon cancer closely follows the paradigm of a single “gatekeeper gene.” Mutations inactivating the APC (adenomatous polyposis coli) gene are found in ∼80% of all human colon tumors and heterozygosity for such mutations produces an autosomal dominant colon cancer predisposition in humans and in murine models. However, this tight association between a single genotype and phenotype belies a complex association of genetic and epigenetic factors that together generate the broad phenotypic spectrum of both familial and sporadic colon cancers. In this Chapter, we give a general overview of the structure, function and outstanding issues concerning the role of Apc in human and experimental colon cancer. The availability of increasingly close models for human colon cancer in genetically tractable animal species enables the discovery and eventual molecular identification of genetic modifiers of the Apc-mutant phenotypes, connecting the central role of Apc in colon carcinogenesis to the myriad factors that ultimately determine the course of the disease.


Colon Cancer Familial Adenomatous Polyposis Adenomatous Polyposis Coli Adenomatous Polyposis Coli Gene Tumor Multiplicity 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Jemal A, Siegel R, Ward E et al. Cancer statistics. CA Cancer J Clin 2006; 56:106–130.PubMedCrossRefGoogle Scholar
  2. 2.
    Grosch S, Maier TJ, Schiffmann S et al. Cyclooxygenase-2 (COX-2)-independent anticarcinogenic effects of selective COX-2 inhibitors. J Natl Cancer Inst 2006; 98:736–747.PubMedCrossRefGoogle Scholar
  3. 3.
    O’Connell JB, Maggard MA, Ko CY. Colon cancer survival rates with the new american joint committee on cancer sixth edition staging. J Natl Cancer Inst 2004; 96:1420–1425.PubMedCrossRefGoogle Scholar
  4. 4.
    Radtke F, Clevers H. Self-renewal and cancer of the gut: two sides of a coin. Science 2005; 307:1904–1909.PubMedCrossRefGoogle Scholar
  5. 5.
    Wasan HS, Park H S, Liu K C et al. APC in the regulation of intestinal crypt fission. J Pathol 1998; 185:246–255.PubMedCrossRefGoogle Scholar
  6. 6.
    Greaves LC, Preston SL, Tadrous P J et al. Mitochondrial DNA mutations are established in human colonic stem cells and mutated clones expand by crypt fission. Proc Natl Acad Sci USA 2006; 103:714–719.PubMedCrossRefGoogle Scholar
  7. 7.
    Ponder BAJ, Schmidt GH, Wilkinson MM et al. Derivation of mouse intestinal crypts from single progenitor cells. Nature 1985; 313:689–691.PubMedCrossRefGoogle Scholar
  8. 8.
    Kim KM, Shibata D. Methylation reveals a niche: stem cell succession in human colon crypts. Oncogene 2002; 21:5441–5449.PubMedCrossRefGoogle Scholar
  9. 9.
    Fujita Y, Cheung AT, Kieffer TJ. Harnessing the gut to treat diabetes. Pediatr Diabetes 2004; 5(Suppl 2):57–69.PubMedCrossRefGoogle Scholar
  10. 10.
    Potten CS, Morris RJ. Epithelial stem cells in vivo. J Cell Sci Suppl 1988; 10:45–62.PubMedGoogle Scholar
  11. 11.
    Cheng H, Leblond CP. Origin, differentiation and renewal of the four main epithelial cell types in the mouse small intestine. V. Unitarian theory of the origin of the four epithelial cell types. Am J Anat 1974; 141:537–562.PubMedCrossRefGoogle Scholar
  12. 12.
    Potten CS. Epithelial cell growth and differentiation. II. Intestinal apoptosis. Am J Physiol Gastrointest Liver Physiol 1997; 273:G253–G257.Google Scholar
  13. 13.
    Clarke MF, Fuller M. Stem sells and cancer: Two faces of Eve. Cell 2006; 124:1111–1115.PubMedCrossRefGoogle Scholar
  14. 14.
    Till JE, Siminovitch L, McCulloch EA. The effect of plethora on growth and differentiation of normal hemopoietic colony-forming cells transplanted in mice of genotype W/Wv. Blood 1967; 29:102–113.PubMedGoogle Scholar
  15. 15.
    Reya T, Morrison SJ, Clarke MF et al. Stem cells, cancer and cancer stem cells. Nature 2001; 414:105–111.PubMedCrossRefGoogle Scholar
  16. 16.
    Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 1997; 3:730–737.PubMedCrossRefGoogle Scholar
  17. 17.
    Al Hajj M, Wicha MS, Benito-Hernandez A et al. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 2003; 100:3983–3988.CrossRefGoogle Scholar
  18. 18.
    Matsui W, Huff CA, Wang Q et al. Characterization of clonogenic multiple myeloma cells. Blood 2004; 103:2332–2336.PubMedCrossRefGoogle Scholar
  19. 19.
    Singh SK, Clarke ID, Terasaki M et al. Identification of a cancer stem cell in human brain tumors. Cancer Res 2003; 63:5821–5828.PubMedGoogle Scholar
  20. 20.
    Collins AT, Berry PA, Hyde C et al. Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res 2005; 65:10946–10951.PubMedCrossRefGoogle Scholar
  21. 21.
    O’Brien CA, Pollett A, Gallinger S et al. A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 2007; 445:106–110.PubMedCrossRefGoogle Scholar
  22. 22.
    Ricci-Vitiani L, Lombardi DG, Pilozzi E et al. Identification and expansion of human colon-cancer-initiating cells. Nature 2006.Google Scholar
  23. 23.
    Polyak K, Hahn WC. Roots and stems: stem cells in cancer. Nat Med 2006; 12:296–300.PubMedCrossRefGoogle Scholar
  24. 24.
    Shih IM, Wang TL, Traverso G et al. Top-down morphogenesis of colorectal tumors. Proc Natl Acad Sci USA 2001; 98:2640–2645.PubMedCrossRefGoogle Scholar
  25. 25.
    Kim KM, Calabrese P, Tavare S et al. Enhanced stem cell survival in familial adenomatous polyposis. Am J Pathol 2004; 164:1369–1377.PubMedGoogle Scholar
  26. 26.
    Wood DA, Robbins GF, Zippin C et al. Staging of cancer of the colon and cancer of the rectum. Cancer 1979; 43:961–968.PubMedCrossRefGoogle Scholar
  27. 27.
    Gospodarowicz MK, Miller D, Groome PA et al. The process for continuous improvement of the TNM classification. Cancer 2004; 100:1–5.PubMedCrossRefGoogle Scholar
  28. 28.
    Bond JH. Colon Polyps and Cancer. Endoscopy 2003; 27–35.Google Scholar
  29. 29.
    Chan TL, Zhao W, Cancer GP et al. BRAF and KRAS mutations in colorectal hyperplastic polyps and serrated adenomas. Cancer Res 2003; 63:4878–4881.PubMedGoogle Scholar
  30. 30.
    Gardner EJ. A genetic and clinical study of intestinal polyposis, a predisposing factor for carcinoma of the colon and rectum. Am J Hum Genet 1951; 3:167–176.PubMedGoogle Scholar
  31. 31.
    Shoemaker AR, Gould KA, Luongo C et al. Studies of neoplasia in the Min mouse. Biochim Biophys Acta 1997; 1332:F25–F48.PubMedGoogle Scholar
  32. 32.
    Herrera L, Kakati S, Gibas L et al. Brief clinical report: gardner syndrome in a man with an interstitial deletion of 5q. Am J Hum Genet 1986; 25:473–476.Google Scholar
  33. 33.
    Bodmer WF, Bailey CJ, Bodmer J et al. Localization of the gene for familial adenomatous polyposis on chromosome 5. Nature 1987; 328:614–616.PubMedCrossRefGoogle Scholar
  34. 34.
    Kinzler KW, Nilbert MC, Su LK et al. Identification of FAP locus genes from chromosome 5q21. Science 1991; 253:661–665.PubMedCrossRefGoogle Scholar
  35. 35.
    Nishisho I, Nakamura Y, Miyoshi Y et al. Mutation of chromosome 5q21 genes in FAP and colorectal cancer patients. Science 1991; 253:665–668.PubMedCrossRefGoogle Scholar
  36. 36.
    Joslyn G, Carlson M, Thliveris A et al. Identification of deletion mutations and three new genes at the familial polyposis locus. Cell 1991; 66:601–613.PubMedCrossRefGoogle Scholar
  37. 37.
    Groden J, Thliveris A, Samowitz W et al. Identification and characterization of the familial adenomatous polyposis coli gene. Cell 1991; 66:589–600.PubMedCrossRefGoogle Scholar
  38. 38.
    Fearnhead NS, Britton MP, Bodmer WF. The ABC of APC. Hum Mol Genet 2001; 10:721–733.PubMedCrossRefGoogle Scholar
  39. 39.
    Horii A, Nakatsuru S, Miyoshi Y et al. Frequent somatic mutations of the APC gene in human pancreatic cancer. Cancer Res 1992; 52:6696–6698.PubMedGoogle Scholar
  40. 40.
    Clement G, Bosman FT, Fontolliet C et al. Monoallelic methylation of the APC promoter is altered in normal gastric mucosa associated with neoplastic lesions. Cancer Res 2004; 64:6867–6873.PubMedCrossRefGoogle Scholar
  41. 41.
    Su LK, Vogelstein B, Kinzler KW: Association of the APC tumor suppressor protein with catenins. Science 1993; 262:1734–1737.PubMedCrossRefGoogle Scholar
  42. 42.
    Rubinfeld B, Souza B, Albert I et al. Association of the APC gene product with β-catenin. Science 1993; 262:1731–1734.PubMedCrossRefGoogle Scholar
  43. 43.
    Fearnhead NS, Wilding JL, Bodmer WF. Genetics of colorectal cancer: hereditary aspects and overview of colorectal tumorigenesis. Br Med Bull 2002; 64:27–43.PubMedCrossRefGoogle Scholar
  44. 44.
    Noubissi FK, Elcheva I, Bhatia N et al. CRD-BP mediates stabilization of [beta]TrCP1 and c-myc mRNA in response to [beta]-catenin signalling. Nature 2006; 441:898–901.PubMedCrossRefGoogle Scholar
  45. 45.
    Harada N, Tarnai Y, Ishikawa T et al. Intestinal polyposis in mice with a dominant stable mutation of the beta-catenin gene. EMBO J 1999; 18:5931–5942.PubMedCrossRefGoogle Scholar
  46. 46.
    Romagnolo B, Berrebi D, Saadi-Keddoucci S et al. Intestinal dysplasia and adenoma in transgenic mice after overexpression of an activated β-catenin. Cancer Res 1999; 59:3875–3879.PubMedGoogle Scholar
  47. 47.
    Thliveris A, Samowitz W, Matsunami N et al. Demonstration of promoter activity and alternative splicing in the region 5′ to exon 1 of the APC gene. Cancer Res 1994; 54:2991–2995.PubMedGoogle Scholar
  48. 48.
    Bardos J, Sulekova Z, Ballhausen WG. Novel exon connections of the brain-specific (BS) exon of the adenomatous polyposis coli gene. Int J Cancer 1997; 73: 137–142.PubMedCrossRefGoogle Scholar
  49. 49.
    Pyles RB, Santoro IM, Groden J et al. Novel protein isoforms of the APC tumor suppressor in neural tissue. Oncogene 1998; 16:77–82.PubMedCrossRefGoogle Scholar
  50. 50.
    Rubinfeld B, Albert I, Porfiri E et al. Binding of GSK3β to the APC-β-catenin complex and regulation of complex assembly. Science 1996; 272: 1023–1026.PubMedCrossRefGoogle Scholar
  51. 51.
    Behrens J, Jerchow BA, Wurtele M et al. Functional interaction of an axin homolog, conductin, with β-catenin, APC and GSK3β. Science 1998; 280:596–599.PubMedCrossRefGoogle Scholar
  52. 52.
    Zumbrunn J, Kinoshita K, Hyman AA et al. Binding of the adenomatous polyposis coli protein to microtubules increases microtubule stability and is regulated by GSK3[beta] phosphorylation. Curr Biol 2001; 11:44–49.PubMedCrossRefGoogle Scholar
  53. 53.
    Polakis P. The adenomatous polyposis coli (APC) tumor suppressor. Biochim Biophys Acta 1997; 1332:FI27–F148.Google Scholar
  54. 54.
    Heppner Goss K, Trzepacz C, Tuohy TM et al. Attenuated APC alleles produce functional protein from internal translation initiation. Proc Natl Acad Sci USA 2002; 99:8161–8166.CrossRefGoogle Scholar
  55. 55.
    Jimbo T, Kawasaki Y, Koyama R et al. Identification of a link between the tumour suppressor APC and the kinesin superfamily. Nat Cell Biol 2002; 4:323–327.PubMedCrossRefGoogle Scholar
  56. 56.
    Aoki K, Taketo MM. Adenomatous polyposis coli (APC): a multi-functional tumor suppressor gene. J Cell Sci 2007; 120:3327–3335.PubMedCrossRefGoogle Scholar
  57. 57.
    Rowan AJ, Lamlum H, Ilyas M et al. APC mutations in sporadic colorectal tumors: A mutational “hotspot” and interdependence of the “two hits”. Proc Natl Acad Sci USA 2000; 97:3352–3357.PubMedCrossRefGoogle Scholar
  58. 58.
    Albuquerque C, Breukel C, van der LR et al. The ‘just-right’ signaling model: APC somatic mutations are selected based on a specific level of activation of the beta-catenin signaling cascade. Hum Mol Genet 2002; 11:1549–1560.PubMedCrossRefGoogle Scholar
  59. 59.
    Crabtree M, Sieber OM, Lipton L et al. 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 2003; 22:4257–4265.PubMedCrossRefGoogle Scholar
  60. 60.
    Crabtree MD, Tomlinson IPM, Hodgson SV et al. Explaining variation in familial adenomatous polyposis: relationship between genotype and phenotype and evidence for modifier genes. Gut 2002; 51:420–423.PubMedCrossRefGoogle Scholar
  61. 61.
    Soliman AS, Bondy ML, El Badawy SA et al. Contrasting molecular pathology of colorectal carcinoma in Egyptian and Western patients. Br J Cancer 2001; 85:1037–1046.PubMedCrossRefGoogle Scholar
  62. 62.
    Moser AR, Pitot HC, Dove WF. A dominant mutation that predisposes to multiple intestinal neoplasia in the mouse. Science 1990; 247:322–324.PubMedCrossRefGoogle Scholar
  63. 63.
    Su LK, Kinzler KW, Vogelstein B et al. Multiple intestinal neoplasia caused by a mutation in the murine homolog of the APC gene. Science 1992; 256:668–670.PubMedCrossRefGoogle Scholar
  64. 64.
    Sasai H, Masaki M, Wakitani K. Suppression of polypogenesis in a new mouse strain with a truncated ApcDelta474 by a novel COX-2 inhibitor, JTE-522. Carcinogenesis 2000; 21:953–958.PubMedCrossRefGoogle Scholar
  65. 65.
    Colnot S, Niwa-Kawakita M, Hamard G et al. Colorectal cancers in a new mouse model of familial adenomatous polyposis: influence of genetic and environmental modifiers. Lab Invest 2004; 84: 1619–1630.PubMedCrossRefGoogle Scholar
  66. 66.
    Oshima M, Oshima H, Kitagawa K et al. Loss of Apc heterozygosity and abnormal tissue building in nascent intestinal polyps in mice carrying a truncated Apc gene. Proc Natl Acad Sci USA 1995; 92:4482–4486.PubMedCrossRefGoogle Scholar
  67. 67.
    Ishikawa T, Tarnai Y, Li Q et al. Requirement for tumor suppressor Apc in the morphogenesis of anterior and ventral mouse embryo. Dev Biol 2003; 253:230–246.PubMedCrossRefGoogle Scholar
  68. 68.
    Niho N, Takahashi M, Kitamura T et al. Concomitant suppression of hyperlipidemia and intestinal polyp formation in Apc-deficient mice by peroxisome proliferator-activated receptor ligands. Cancer Res 2003; 63:6090–6095.PubMedGoogle Scholar
  69. 69.
    Fodde R, Edelmann W, Yang K et al. A targeted chain-termination mutation in the mouse Apc gene results in multiple intestinal tumors. Proc Natl Acad Sci USA 1994; 91:8969–8973.PubMedCrossRefGoogle Scholar
  70. 70.
    Smits R, Kielman MF, Breukel C et al. Apc1638T: a mouse model delineating critical domains of the adenomatous polyposis coli protein involved in tumorigenesis and development. Genes Dev 1999; 13:1309–1321.PubMedCrossRefGoogle Scholar
  71. 71.
    Li Q Ishikawa TO, Oshima M et al. The threshold level of adenomatous polyposis coli protein for mouse intestinal tumorigenesis. Cancer Res 2005; 65:8622–8627.PubMedCrossRefGoogle Scholar
  72. 72.
    Haigis KM, Hoff PD, White A et al. Tumor regionality in the mouse intestine reflects the mechanism of loss of Apc function. Proc Natl Acad Sci USA 2004; 101:9769–9773.PubMedCrossRefGoogle Scholar
  73. 73.
    Baran AA, Silverman KA, Zeskand J et al. The modifier of Min 2 (Mom2) locus: embryonic lethality of a mutation in the Atp5a1 gene suggests a novel mechanism of polyp suppression. Genome Res 2007; 17:566–576.PubMedCrossRefGoogle Scholar
  74. 74.
    Gounari F, Chang R, Cowan J et al. Loss of adenomatous polyposis coli gene function disrupts thymic development. Nat Immunol 2005; 6:800–809.PubMedCrossRefGoogle Scholar
  75. 75.
    Shibata H, Toyama K, Shioya H et al. Rapid colorectal adenoma formation initiated by conditional targeting of the Apc gene. Science 1997; 278:120–123.PubMedCrossRefGoogle Scholar
  76. 76.
    Colnot S, Decaens T, Niwa-Kawakita M et al. Liver-targeted disruption of Apc in mice activates beta-catenin signaling and leads to hepatocellular carcinomas. Proc Natl Acad Sci USA 2004; 101: 17216–17221.PubMedCrossRefGoogle Scholar
  77. 77.
    Sansom OJ, Griffiths DF, Reed KR et al. Apc deficiency predisposes to renal carcinoma in the mouse. Oncogene 2005; 24:8205–8210.PubMedCrossRefGoogle Scholar
  78. 78.
    Sansom OJ, Reed KR, Hayes AJ et al. Loss of Apc in vivo immediately perturbs Wnt signaling, differentiation and migration. Genes Dev 2004; 18:1385–1390.PubMedCrossRefGoogle Scholar
  79. 79.
    Andreu P, Colnot S, Godard C et al. Crypt-restricted proliferation and commitment to the Paneth cell lineage following Apc loss in the mouse intestine. Development 2005; 132:1443–1451.PubMedCrossRefGoogle Scholar
  80. 80.
    Sansom OJ, Meniel VS, Muncan V et al. Myc deletion rescues Apc deficiency in the small intestine. Nature 2007; 446:676–679.PubMedCrossRefGoogle Scholar
  81. 81.
    Bissahoyo A, Pearsall RS, Hanlon K et al. Azoxymethane is a genetic background-dependent colorectal tumor initiator and promoter in mice: effects of dose, route and diet. Toxicol Sci 2005; Dec;88(2):340–5. Epub 2005 Sep 8.PubMedCrossRefGoogle Scholar
  82. 82.
    Shoemaker AR, Moser AR, Dove WF. N-ethyl-N-nitrosourea treatment of multiple intestinal neoplasia (Min) mice: age-related effects on the formation of intestinal adenomas, cystic crypts and epidermoid cysts. Cancer Res 1995; 55:4479–4485.PubMedGoogle Scholar
  83. 83.
    Biswas S, Chytil A, Washington K et al. Transforming growth factor beta receptor type II inactivation promotes the establishment and progression of colon cancer. Cancer Res 2004; 64:4687–4692.PubMedCrossRefGoogle Scholar
  84. 84.
    Oshima H, Oshima M, Kobayashi M et al. Morphological and molecular processes of polyp formation in ApcΔ716 knockout mice. Cancer Res 1997; 57:1644–1649.PubMedGoogle Scholar
  85. 85.
    Cormier RT, Dove WF. Dnmt1N/+ reduces the net growth rate and multiplicity of intestinal adenomas in C57BL/6-Multiple intestinal neoplasia (Min)/+ mice independently of p53 but demonstrates strong synergy with the Modifier of Min 1AKR resistance allele. Cancer Res 2000; 60:3965–3970.PubMedGoogle Scholar
  86. 86.
    Preston SL, Wong WM, Chan AO et al. Bottom-up histogenesis of colorectal adenomas: origin in the monocryptal adenoma and initial expansion by crypt fission. Cancer Res 2003; 63:3819–3825.PubMedGoogle Scholar
  87. 87.
    Leedham S, Wright N. Expansion of a mutated clone-from stem cell to tumour. J Clin Pathol 2008; Feb;61(2):164–71. Epub 2007 Apr 27.PubMedCrossRefGoogle Scholar
  88. 88.
    Goodman DG, Ward JM, Squire RA et al. Neoplastic and Nonneoplastic Lesions in Aging Osborne—Mendel Rats. Toxicology and Applied Pharmacology 1980; 55:433–447.PubMedCrossRefGoogle Scholar
  89. 89.
    Miyamoto M, Takizawa S. Colon carcinoma of highly inbred rats. J Natl Cancer Inst 1975; 55:1471–1472.PubMedGoogle Scholar
  90. 90.
    Corpet DE, Pierre F. How good are rodent models of carcinogenesis in predicting efficacy in humans? A systematic review and meta-analysis of colon chemoprevention in rats, mice and men. Eur J Cancer 2005; 41:1911–1922.PubMedCrossRefGoogle Scholar
  91. 91.
    Zan Y, Haag JD, Chen KS et al. Production of knockout rats using ENU mutagenesis and a yeast-based screening assay. Nat Biotechnol 2003; 21:645–651.PubMedCrossRefGoogle Scholar
  92. 92.
    Smits BM, Mudde JB, van de BJ et al. Generation of gene knockouts and mutant models in the laboratory rat by ENU-driven target-selected mutagenesis. Pharmacogenet Genomics 2006; 16:159–169.PubMedGoogle Scholar
  93. 93.
    Amos-Landgraf JM, Kwong LN, Kendziorski CM et al. A target-selected Apc-mutant rat kindred enhances the modeling of familial human colon cancer. Proc Natl Acad Sci USA 2007; 104:4036–4041.PubMedCrossRefGoogle Scholar
  94. 94.
    Haramis AP, Hurlstone A, Van D et al. Adenomatous polyposis coli-deficient zebrafish are susceptible to digestive tract neoplasia. EMBO Rep 2006; 7:444–449.PubMedGoogle Scholar
  95. 95.
    McCartney BM, Price MH, Webb RL et al. Testing hypotheses for the functions of APC family proteins using null and truncation alleles in Drosophila. Development 2006; 133:2407–2418.PubMedCrossRefGoogle Scholar
  96. 96.
    Hamada F, Murata Y, Nishida A et al. Identification and characterization of E-APC, a novel Drosophila homologue of the tumour suppressor APC. Genes to Cells 1999; 4:465–474.PubMedCrossRefGoogle Scholar
  97. 97.
    Rocheleau CE, Downs WD, Lin R et al. Wnt Signaling and an APC-Related Gene Specify Endoderm in Early C. elegans Embryos. Cell 1997; 90:707–716.PubMedCrossRefGoogle Scholar
  98. 98.
    Mizumoto K, Sawa H. Cortical beta-catenin and APC regulate asymmetric nuclear beta-catenin localization during asymmetric cell division in C. elegans. Dev Cell 2007; 12:287–299.PubMedCrossRefGoogle Scholar
  99. 99.
    Luongo C, Moser AR, Gledhill S et al. Loss of Apc+ in intestinal adenomas from Min mice. Cancer Res 1994; 54:5947–5952.PubMedGoogle Scholar
  100. 100.
    Haigis KM, Dove WF. A Robertsonian translocation suppresses a somatic recombination pathway to loss of heterozygosity. Nat Genet 2003; 33:33–39.PubMedCrossRefGoogle Scholar
  101. 101.
    Sieber OM, Heinimann K, Gorman P et al. Analysis of chromosomal instability in human colorectal adenomas with two mutational hits at APC. Proc Natl Acad Sci USA 2002; 99:16910–16915.PubMedCrossRefGoogle Scholar
  102. 102.
    Haigis KM, Caya JG, Reichelderfer M et al. Intestinal adenomas can develop with a stable karyotype and stable microsatellites. Proc Natl Acad Sci USA 2002; 99:8927–8931.PubMedGoogle Scholar
  103. 103.
    Cavenee WK, Dryja TP, Phillips RA et al. Expression of recessive alleles by chromosomal mechanisms in retinoblastoma. Nature 1983; 305:779–784.PubMedCrossRefGoogle Scholar
  104. 104.
    Hagstrom SA, Dryja TP. Mitotic recombination map of 13cen–13q14 derived from an investigation of loss of heterozygosity in retinoblastomas. Proc Natl Acad Sci USA 1999; 96:2952–2957.PubMedCrossRefGoogle Scholar
  105. 105.
    Thiagalingam S, Laken S, Willson JK et al. Mechanisms underlying losses of heterozygosity in human colorectal cancers. Proc Natl Acad Sci USA 2001; 98:2698–2702.PubMedCrossRefGoogle Scholar
  106. 106.
    Shih IM, Zhou W, Goodman SN et al. Evidence that genetic instability occurs at an early stage of colorectal tumorigenesis. Cancer Res 2001; 61:818–822.PubMedGoogle Scholar
  107. 107.
    Xinarianos G, McRonald FE, Risk JM et al. Frequent genetic and epigenetic abnormalities contribute to the deregulation of cytoglobin in nonsmall cell lung cancer. Hum Mol Genet 2006; 15:2038–2044.PubMedCrossRefGoogle Scholar
  108. 108.
    Cardoso J, Molenaar L, de Menezes RX et al. Chromosomal instability in MYH-and APC-mutant adenomatous polyps. Cancer Res 2006; 66:2514–2519.PubMedCrossRefGoogle Scholar
  109. 109.
    Nowak MA, Komarova NL, Sengupta A et al. The role of chromosomal instability in tumor initiation. Proc Natl Acad Sci USA 2002; 99:16226–16231.PubMedCrossRefGoogle Scholar
  110. 110.
    Komarova NL, Wodarz D. The optimal rate of chromosome loss for the inactivation of tumor suppressor genes in cancer. Proc Natl Acad Sci USA 2004; 101:7017–7021.PubMedCrossRefGoogle Scholar
  111. 111.
    Tomlinson IPM, Novelli MR, Bodmer WF. The mutation rate and cancer. Proc Natl Acad Sci USA 1996; 93:14800–14803.PubMedCrossRefGoogle Scholar
  112. 112.
    Green RA, Kaplan KB. Chromosome instability in colorectal tumor cells is associated with defects in microtubule plus-end attachments caused by a dominant mutation in APC. The Journal of Cell Biology 2003; 163:949–961.PubMedCrossRefGoogle Scholar
  113. 113.
    Tighe A, Johnson VL, Taylor SS. Truncating APC mutations have dominant effects on proliferation, spindle checkpoint control, survival and chromosome stability. J Cell Sci 2004; 117:6339–6353.PubMedCrossRefGoogle Scholar
  114. 114.
    Li Z, Nathke IS. Tumor-associated NH2-terminal fragments are the most stable part of the adenomatous polyposis coli protein and can be regulated by interactions with COOH-terminal domains. Cancer Res 2005; 65:5195–5204.PubMedCrossRefGoogle Scholar
  115. 115.
    Mahmoud NN, Boolbol SK, Bilinski RT et al. Apc Gene Mutation Is Associated with a Dominant-Negative Effect upon Intestinal Cell Migration. Cancer Res 1997; 57:5045–5050.Google Scholar
  116. 116.
    Carothers AM, Melstrom KA Jr, Mueller JD et al. Progressive changes in adherens junction structure during intestinal adenoma formation in Apc mutant mice. J Biol Chem 2001; 276:39094–39102.PubMedCrossRefGoogle Scholar
  117. 117.
    Moran AE, Hunt DH, Javid SH et al. Apc deficiency is associated with increased Egfr activity in the intestinal enterocytes and adenomas of C57BL/6J-Min/+ mice. J Biol Chem 2004; 279:43261–43272.PubMedCrossRefGoogle Scholar
  118. 118.
    Oshima M, Oshima H, Kobayashi M et al. Evidence against dominant negative mechanisms of intestinal polyp formation by Apc gene mutations. Cancer Res 1995; 55:2719–2722.PubMedGoogle Scholar
  119. 119.
    Sieber OM, Lamlum H, Crabtree MD et al. Whole-gene APC deletions cause classical familial adenomatous polyposis, but not attenuated polyposis or “multiple” colorectal adenomas. Proc Natl Acad Sci USA 2002; 99:2954–2958.PubMedCrossRefGoogle Scholar
  120. 120.
    Michils G, Tejpar S, Thoelen R et al. Large deletions of the APC gene in 15% of mutation-negative patients with classical polyposis (FAP): a Belgian study. Hum Mutat 2005; 25:125–134.PubMedCrossRefGoogle Scholar
  121. 121.
    Kwong LN, Shedlovsky A, Biehl BS et al. Identification of Mom7, a novel modifier of ApcMin/+ on mouse Chromosome 18. Genetics 2007; 176:1237–1244.PubMedCrossRefGoogle Scholar
  122. 122.
    Shoemaker AR, Moser AR, Midgley CA et al. A resistant genetic background leading to incomplete penetrance of intestinal neoplasia and reduced loss of heterozygosity in ApcMin/+ mice. Proc Natl Acad Sci USA 1998; 95:10826–10831.PubMedCrossRefGoogle Scholar
  123. 123.
    Dietrich WF, Lander ES, Smith JS et al. Genetic identification of Mom-1, a major modifier locus affecting Min-induced intestinal neoplasia in the mouse. Cell 1993; 75:631–639.PubMedCrossRefGoogle Scholar
  124. 124.
    MacPhee M, Chepenik KP, Liddell RA et al. The secretory phospholipase A2 gene is a candidate for the Mom1 locus, a major modifier of ApcMin-induced intestinal neoplasia. Cell 1995; 81:957–966.PubMedCrossRefGoogle Scholar
  125. 125.
    Cormier RT, Hong KH, Halberg RB et al. Secretory phospholipase Pla2g2aconfers resistanceto intestinal tumorigenesis. Nat Genet 1997; 17:88–91.PubMedCrossRefGoogle Scholar
  126. 126.
    Cormier RT, Bilger A, Lillich AJ et al. The Mom1AKR intestinal tumor resistance region consists of Pla2g2a and a locus distal to D4Mit64. Oncogene 2000; 19:3182–3192.PubMedCrossRefGoogle Scholar
  127. 127.
    Belinsky GS, Rajan TV, Saria EA et al. Expression of secretory phospholipase A2 in colon tumor cells potentiates tumor growth. Mol Carcinog 2007; 46:106–116.PubMedCrossRefGoogle Scholar
  128. 128.
    Dove W. Aurora and the hunt for cancer-modifying genes. Nat Genet 2003; 34:353–354.PubMedCrossRefGoogle Scholar
  129. 129.
    Chan TA, Morin PJ, Vogelstein B et al. Mechanisms underlying nonsteroidal antiinflammatory drug-mediated apoptosis. Proc Natl Acad Sci USA 1998; 95:681–686.PubMedCrossRefGoogle Scholar
  130. 130.
    Tomlinson IP, Beck NE, Neale K et al. Variants at the secretory phospholipase A2 (PLA2G2A) locus: analysis of associations with familial adenomatous polyposis and sporadic colorectal tumours. Ann Hum Genet 1996; 60(Pt 5):369–376.PubMedCrossRefGoogle Scholar
  131. 131.
    Spirio LN, Kutchera W, Winstead MV et al. Three secretory phospholipase A2 genes that map to human chromosome 1P35–36 are not mutated in individuals with attenuated adenomatous polyposis coli. Cancer Res 1996; 56:955–958.PubMedGoogle Scholar
  132. 132.
    Riggins GJ, Markowitz S, Wilson JK et al. Absence of secretory phospholipase A2 gene alterations in human colorectal cancer. Cancer Res 1995; 55:5184–5186.PubMedGoogle Scholar
  133. 133.
    Nimmrich I, Friedl W, Kruse R et al. Loss of the PLA2G2A gene in a sporadic colorectal tumor of a patient with a PLA2G2A germline mutation and absence of PLA2G2A germline alterations in patients with FAP. Hum Genet 1997; 100:345–349.PubMedCrossRefGoogle Scholar
  134. 134.
    Leung SY, Chen X, Chu KM et al. Phospholipase A2 group IIA expression in gastric adenocarcinoma is associated with prolonged survival and less frequent metastasis. Proc Natl Acad Sci USA 2002; 99:16203–16208.PubMedCrossRefGoogle Scholar
  135. 135.
    Silverman KA, Koratkar R, Siracusa LD et al. Identification of the modifier of Min 2 (Mom2) locus, a new mutation that influences Apc-induced intestinal neoplasia. Genome Res 2002; 12:88–97.PubMedCrossRefGoogle Scholar
  136. 136.
    Haines J, Johnson V, Pack K et al. Genetic basis of variation in adenoma multiplicity in ApcMin/+ Mom1S mice. Proc Natl Acad Sci USA 2005; 102:2868–2873.PubMedCrossRefGoogle Scholar
  137. 137.
    Shao C, Stambrook PJ, Tischfield JA. Mitotic recombination is suppressed by chromosomal divergence in hybrids of distantly related mouse strains. Nat Genet 2001; 28:169–172.PubMedCrossRefGoogle Scholar
  138. 138.
    Rao CV, Yang YM, Swamy MV et al. Colonic tumorigenesis in BubR1+/-ApcMin/+ compound mutant mice is linked to premature separation of sister chromatids and enhanced genomic instability. PNAS 2005; 102:4365–4370.PubMedCrossRefGoogle Scholar
  139. 139.
    Sakatani T, Kaneda A, Iacobuzio-Donahue CA et al. Loss of imprinting of Igf2 alters intestinal maturation and tumorigenesis in mice. Science 2005; 307:1976–1978.PubMedCrossRefGoogle Scholar
  140. 140.
    Cui H, Cruz-Correa M, Giardiello FM et al. Loss of IGF2 imprinting: A potential marker of colorectal cancer risk. Science 2003; 299:1753–1755.PubMedCrossRefGoogle Scholar
  141. 141.
    Aoki K, Tarnai Y, Horiike S et al. Colonic polyposis caused by mTOR-mediated chromosomal instability in Apc+/Delta716 Cdx2+/− compound mutant mice. Nat Genet 2003; 35:323–330.PubMedCrossRefGoogle Scholar
  142. 142.
    Goss KH, Risinger MA, Kordich JJ et al. Enhanced tumor formation in mice heterozygous for Blm mutation. Science 2002; 297:2051–2053.PubMedCrossRefGoogle Scholar
  143. 143.
    Luo G, Santoro IM, McDaniel LD et al. Cancer predisposition caused by elevated mitotic recombination in Bloom mice. Nat Genet 2000; 26:424–429.PubMedCrossRefGoogle Scholar
  144. 144.
    Mann MB, Hodges CA, Barnes E et al. Defective sister-chromatid cohesion, aneuploidy and cancer predisposition in a mouse model of type II Rothmund-Thomson syndrome. Hum Mol Genet 2005; 14:813–825.PubMedCrossRefGoogle Scholar
  145. 145.
    Sansom OJ, Berger J, Bishop SM et al. Deficiency of Mbd2 suppresses intestinal tumorigenesis. Nat Genet 2003; 34:145–147.PubMedCrossRefGoogle Scholar
  146. 146.
    Millar CB, Guy J, Sansom OJ et al. Enhanced CpG mutability and tumorigenesis in MBD4-deficient mice. Science 2002; 297:403–405.PubMedCrossRefGoogle Scholar
  147. 147.
    Batlle E, Bacani J, Begthel H et al. EphB receptor activity suppresses colorectal cancer progression. Nature 2005; 435:1126–1130.PubMedCrossRefGoogle Scholar
  148. 148.
    Leppert M, Dobbs M, Scambier P et al. The gene for familial polyposis coli maps to the long arm of chromosome 5. Science 1987; 238:1411–1413.PubMedCrossRefGoogle Scholar
  149. 149.
    Oshima M, Oshima H, Kitagawa K et al. Loss of Apc heterozygosity and abnormal tissue building in nascent intestinal polyps in mice carrying a truncated Apc gene. Proc Natl Acad Sci USA 1995; 92:4482–4486.PubMedCrossRefGoogle Scholar
  150. 150.
    Ishikawa TO, Jain NK, Taketo MM et al. Imaging cyclooxygenase-2 (Cox-2) gene expression in living animals with a luciferase knock-in reporter gene. Mol Imaging Biol 2006; 8:171–187.PubMedCrossRefGoogle Scholar
  151. 151.
    Koratkar R, Silverman KA, Pequignot E et al. Analysis of reciprocal congenic lines reveals the C3HIHeJ genome to be highly resistant to ApcMin intestinal tumorigenesis. Genomics 2004; 84:844–852.PubMedCrossRefGoogle Scholar
  152. 152.
    Koratkar R, Pequignot E, Hauck WW et al. The CAST/Ei strain confers significant protection against ApcMin intestinal polyps, independent of the resistant Modifier of Min 1 (Mom1R) locus. Cancer Res 2002; 62:5413–5417.PubMedGoogle Scholar
  153. 153.
    Rudolph KL, Millard M, Bosenberg MW et al. Telomere dysfunction and evolution of intestinal carcinoma in mice and humans. Nat Genet 2001; 28:155–159.PubMedCrossRefGoogle Scholar
  154. 154.
    Baker SM, Harris AC, Tsao JL et al. Enhanced intestinal adenomatous polyp formation in Pms2−/−; Min mice. Cancer Res 1998; 58:1087–1089.PubMedGoogle Scholar
  155. 155.
    Shoemaker AR, Haigis KM, Baker SM et al. Mlh1 deficiency enhances several phenotypes of ApCMin/+ mice. Oncogene 2000; 19:2774–2779.PubMedCrossRefGoogle Scholar
  156. 156.
    Reitmair AH, Cai JC, Bjerknes M et al. MSH2 deficiency contributes to accelerated APC-mediated intestinal tumorigenesis. Cancer Res 1996; 56:2922–2926.PubMedGoogle Scholar
  157. 157.
    Kuraguchi M, Yang K, Wong E et al. The distinct spectra of tumor-associated Apc mutations in mismatch repair-deficient Apc1638N mice define the roles of MSH3 and MSH6 in DNA repair and intestinal tumorigenesis. Cancer Res 2001; 61:7934–7942.PubMedGoogle Scholar
  158. 158.
    Kucherlapati M, Yang K, Kuraguchi M et al. Haploinsufficiency of Flap endonuclease (Fen 1) leads to rapid tumor progression. PNAS 2002; 99:9924–9929.PubMedCrossRefGoogle Scholar
  159. 159.
    Sieber OM, Howarth KM, Thirlwell C et al. Myh deficiency enhances intestinal tumorigenesis in multiple intestinal neoplasia (ApcMin/+) mice. Cancer Res 2004; 64:8876–8881.PubMedCrossRefGoogle Scholar
  160. 160.
    Perreault N, Sackett SD, Katz JP et al. Foxll is a mesenchymal Modifier of Min in carcinogenesis of stomach and colon. Genes and Development 2005; 19:311–315.PubMedCrossRefGoogle Scholar
  161. 161.
    Gutierrez LS, Suckow M, Lawler J et al. Thrombospondin 1—a regulator of adenoma growth and carcinoma progression in the APCMin/+ mouse model. Carcinogenesis 2003; 24: 199–207.PubMedCrossRefGoogle Scholar
  162. 162.
    Nateri AS, Spencer-Dene B, Behrens A. Interaction of phosphorylated c-jun with TCF4 regulates intestinal cancer development. Nature 2005; 437:281–285.PubMedCrossRefGoogle Scholar
  163. 163.
    Hulit J, Wang C, Li Z et al. Cyclin Digenetic heterozygosity regulates colonic epithelial cell differentiation and tumor number in ApcMin mice. Mol Cell Biol 2004; 24:7598–7611.PubMedCrossRefGoogle Scholar
  164. 164.
    Roberts RB, Min L, Washington MK et al. Importance of epidermal growth factor receptor signaling in establishment of adenomas and maintenance of carcinomas during intestinal tumorigenesis. Proc Natl Acad Sci USA 2002; 99:1521–1526.PubMedCrossRefGoogle Scholar
  165. 165.
    Yang WC, Mathew J, Velcich A et al. Targeted Inactivation of the p21WAF1/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; 61:565–569.PubMedGoogle Scholar
  166. 166.
    Philipp-Staheli J, Kim KH, Payne SR et al. Pathway-specific tumor suppression. Reduction of p27 accelerates gastrointestinal tumorigenesis in Apc mutant mice, but not in Smad3 mutant mice. Cancer Cell 2002; 1:355–368.PubMedCrossRefGoogle Scholar
  167. 167.
    Halberg RB, Katzung DS, Hoff PD et al. Tumorigenesis in the multiple intestinal neoplasia mouse: redundancy of negative regulators and specificity of modifiers. Proc Natl Acad Sci USA 2000; 97:3461–3466.PubMedCrossRefGoogle Scholar
  168. 168.
    Wilson CL, Heppner KJ, Labosky PA et al. Intestinal tumorigenesis is suppressed in mice lacking the metalloproteinase rnatrilysin. Proc Natl Acad Sci USA 1997; 94:1402–1407.PubMedCrossRefGoogle Scholar
  169. 169.
    Dinchuk JE, Focht RJ, Kelley JA et al. Absence of posttranslational aspartyl β-hydroxylation of epidermal growth factor domains in mice leads to developmental defects and an increased incidence of intestinal neoplasia. J Biol Chem 2002; 277:12970–12977.PubMedCrossRefGoogle Scholar
  170. 170.
    Smits R, Ruiz P, Diaz-Cano S et al. E-cadherin and adenomatous polyposis coli mutations are synergistic in intestinal tumor initiation in mice. Gastroenterology 2000; 119: 1045–1053.PubMedCrossRefGoogle Scholar
  171. 171.
    Harman FS, Nicol CJ, Marin HE et al. Peroxisome proliferator-activated receptor-[delta] attenuates colon carcinogenesis. Nat Med 2004; 10:481–483.PubMedCrossRefGoogle Scholar
  172. 172.
    Mazelin L, Bernet A, Boned-Bidaud C et al. Netrin-1 controls colorectal tumorigenesis by regulating apoptosis. Nature 2004; 431:80–84.PubMedCrossRefGoogle Scholar
  173. 173.
    Takaku K, Miyoshi H, Matsunaga A et al. Gastric and duodenal polyps in Smad4 (Dpc4) knockout mice. Cancer Res 1999; 59:6113–6117.PubMedGoogle Scholar
  174. 174.
    Ruivenkamp CAL, Csikos T, Kious AM et al. Five new mouse susceptibility to colon cancer loci, Scc11–Scc15. Oncogene 2003; 22:7258–7260.PubMedCrossRefGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2009

Authors and Affiliations

  1. 1.McArdle Laboratory for Cancer ResearchUniversity of WisconsinMadisonUSA
  2. 2.Dana-Farber Cancer InstituteBostonUSA

Personalised recommendations