APC Proteins pp 107-118 | Cite as

Tissue-Specific Tumour Suppression byAPC

  • Owen Sansom
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 656)


One question that has been central to the study of the Apc gene is why the Apc gene ismutated so frequently in colorectal cancer but relatively infrequently in other tumour types. This chapter reviews recent data obtained in mice after conditional deletion of both copies of the Apc gene from adult epithelial tissues with particular focus on the intestinal epithelium. These data suggest that a major reason for the frequent mutation of Apc in colorectal cancer lies in the distinct character of the intestinal epithelium where Apc loss leads to a progenitor-like phenotype. Thus intestinal enterocytes lacking Apc escape the two major selective constraints that usually prevent cells from becoming cancerous in the intestine: they fail to differentiate and fail to migrate so are not sloughed off into the intestinal lumen.


Familial Adenomatous Polyposis Intestinal Epithelium Paneth Cell Adenomatous Polyposis Coli Gene Intestinal Crypt 
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.
    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(5057):668–670.CrossRefPubMedGoogle Scholar
  2. 2.
    Luongo C, Moser AR, Gledhill S et al. Loss of Apc+ in intestinal adenomas from Min mice. Cancer Res 1994; 54(22):5947–5952.PubMedGoogle Scholar
  3. 3.
    Oshima M, Dinchuk JE, Kargman SL et al. Suppression of intestinal polyposis in Apc delta716 knockout mice by inhibition of cyelooxygenase2 (COX-2). Cell 1996; 87(5):803–809.CrossRefPubMedGoogle Scholar
  4. 4.
    Yang K, Edelmann W Fan K et al. A mouse model of human familial adenomatous polyposis. J Exp Zool 1997; 277(3):245–254.CrossRefPubMedGoogle Scholar
  5. 5.
    Sauer B, Henderson N. Site-specific DNA recombination in mammalian cells by the Cre recombinase of bacteriophage PI. Proc Natl Acad Sci USA 1988; 85(14):5166–5170.CrossRefPubMedGoogle Scholar
  6. 6.
    Shibata H, Toyama K, Shioya H et al. Rapid colorectal adenoma formation initiated by conditional targeting of the Apc gene. Science 1997; 278(5335):120–123.CrossRefPubMedGoogle Scholar
  7. 7.
    Soriano P. Generalized lacZ expression with the ROSA26 Cre reporter strain. Nat Genet 1999; 21(1):70–71.CrossRefPubMedGoogle Scholar
  8. 8.
    Marshman E, Booth C, Potten CS. The intestinal epithelial stem cell. Bioessays 2002; 24(1):91–98.CrossRefPubMedGoogle Scholar
  9. 9.
    Bach SP, Renehan AG, Potten CS. Stem cells: the intestinal stem cell as a paradigm. Carcinogenesis 2000; 21(3):469–476.Google Scholar
  10. 10.
    Ireland H, Kemp R, Houghton C et al. Inducible Cre-mediated control of gene expression in the murine gastrointestinal tract: effect of loss of beta-eaten in. Gastroenterology 2004; 126(5):1236–1246.CrossRefPubMedGoogle Scholar
  11. 11.
    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(6):1443–1451.CrossRefPubMedGoogle Scholar
  12. 12.
    Campbell SJ, Carlotti F, Hall PA et al. Regulation of the CYPIAI promoter in transgenic mice: an exquisitely sensitive on-off system for cell specific gene regulation. J Cell Sci 1996; 109(Pt 11):2619–2625.PubMedGoogle Scholar
  13. 13.
    Sansom OJ, Reed KR, Hayes AJ et al. Loss of Apc in vivo immediately perturbs wnt signaling, differentiation and migration. Genes Dev 2004; 18(12):1385–1390.CrossRefPubMedGoogle Scholar
  14. 14.
    Sansom OJ, Reed KR, van de Wetering M et al. Cyclin Dl is not an immediate target of beta-eatenin following apc loss in the intestine. J Biol Chern 2005; 280(31):28463–28467.CrossRefGoogle Scholar
  15. 15.
    Dikovskaya D, Schiffmann D, Newton IP et al. Loss of APC induces polyploidy as a result of a combination of defects in mitosis and apoptosis. J Cell Biol 2007; 176(2):183–195.CrossRefPubMedGoogle Scholar
  16. 16.
    Bienz M, Clevers H. Linking colorectal cancer to Wnt signaling. Cell 2000; 103(2):311–320.CrossRefPubMedGoogle Scholar
  17. 17.
    Pinto D, Gregorieff A, Begthel H et al. Canonical wnt signals are essential for homeostasis of the intestinal epithelium. Genes Dev 2003; 17(14):1709–1713.CrossRefPubMedGoogle Scholar
  18. 18.
    Gregorieff A, Pinto D, Begthel H et al. Expression pattern of wnt signaling components in the adult intestine. Gastroenterology 2005; 129(2):626–638.PubMedGoogle Scholar
  19. 19.
    Reed KR, Sansom OJ, Hayes AJ et al. PPARdelta status and apc-mediated tumourigenesis in the mouse intestine. Oncogene 2004; 23(55):8992–8996.CrossRefPubMedGoogle Scholar
  20. 20.
    He TC, Chan TA, Vogelstein B et al. PPARdelta is an APC-regulated target of nonsteroidal anti-inflammatory drugs. Cell 1999; 99(3):335–345.CrossRefPubMedGoogle Scholar
  21. 21.
    Harman FS, Nicol CJ, Marin HE et al. Peroxisome proliferator-acrivated receptor-delta attenuates colon carcinogenesis. Nat Med 2004; 10(5):481–483.CrossRefPubMedGoogle Scholar
  22. 22.
    Tetsu O, McCormick F. Beta-catenin regulates expression of cyelin D1 in colon carcinoma cells. Nature 1999; 398(6726):422–426.Google Scholar
  23. 23.
    Labbe E, Lock L, Letamendia A et al. Transcriptional cooperation between the transforming growth factor-beta and wnt pathways in mammary and intestinal tumorigenesis. Cancer Res 2007; 67(1):75–84.CrossRefPubMedGoogle Scholar
  24. 24.
    Wilson A, Murphy MJ, Oskarsson T et al. c-myc controls the balance between hematopoietic stem cell self-renewal and differentiation. Genes Dev 2004; 18(22):2747–2763.CrossRefPubMedGoogle Scholar
  25. 25.
    Pelengaris S, Khan M, Evan GI. Suppression of myc-induced apoptosis in beta cells exposes multiple oncogenic properties of myc and triggers carcinogenic progression. CeH 2002; 109(3):321–334.Google Scholar
  26. 26.
    Davis AC, Wims M, Spotts GD et al. A null c-myc mutation causeslethality before 10.5 days of gestation in homozygotes and reduced fertility in heterozygous female mice. Genes Dev 1993; 7(4):671–682.CrossRefPubMedGoogle Scholar
  27. 27.
    Bettess MD, Dubois N, Murphy MJ et al. c-mycis required for the formation of intestinal crypts but dispensable for homeostasis of the adult intestinal epithelium. Mol Cell Biol 2005; 25(17):7868–7878.CrossRefPubMedGoogle Scholar
  28. 28.
    Muncan V, Sansom OJ, Tertoolen L et al. Rapid loss of intestinal crypts upon conditional deletion of the wnt/tcf-i target gene c-myc. Mol Cell Biol 2006; 26(22):8418–8426.CrossRefPubMedGoogle Scholar
  29. 29.
    Sansom OJ, Meniel VS, Muncan V et al. Myc deletion rescues apc deficiency in the small intestine. Nature 2007; 446(7136):676–679.CrossRefPubMedGoogle Scholar
  30. 30.
    Batlle E, Henderson JT, Beghtel H et al. Beta-catenin and TCF mediate cell positioning in the intestinal epithelium by controlling the expression of EphB/ephrinB. Cell 2002; 111(2):251–263.CrossRefPubMedGoogle Scholar
  31. 31.
    Malliri A, Rygiel TP, van der Kammen RA et al. The rae activator tiaml is a writ-responsive gene that modifies intestinal tumor development. J Biol Chern 2006; 281(1):543–548.CrossRefGoogle Scholar
  32. 32.
    Mogensen MM, Tucker JB, Mackie JB et al. The adenomatous polyposis coli protein unambiguously localizes to microtubule plus ends and is involved in establishing parallel arrays of microtubule bundles in highly polarized epithelial cells. J Cell Biol 2002; 157(6):1041–1048.CrossRefPubMedGoogle Scholar
  33. 33.
    Nathke I. Cytoskeleton out of the cupboard: colon cancer and cytoskeletal changes induced by loss of APC. Nat Rev Cancer 2006; 6(12):967–974.CrossRefPubMedGoogle Scholar
  34. 34.
    Kaplan KB, Burds AA, Swedlow JR et al. A role for the adenomatous polyposis coli protein in chromosome segregation. Nat Cell Biol 2001; 3(4):429–432.CrossRefPubMedGoogle Scholar
  35. 35.
    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(10):1309–1321.CrossRefPubMedGoogle Scholar
  36. 36.
    Lee HC, Kim M, Wands JR. Wnt/frizzled signaling in hepatocellular carcinoma. Front Biosci 2006; 11:1901–1915.CrossRefPubMedGoogle Scholar
  37. 37.
    Benhamouche S, Decaens T, Godard C et al. Apc tumor suppressor gene is the “zonation-keeper” of mouse liver. Dev Cell 2006; 10(6):759–770.CrossRefPubMedGoogle Scholar
  38. 38.
    Tan X, Behari J, Cieply B et al. Conditional deletion of beta-catenin reveals its role in liver growth and regeneration. Gastroenterology 2006; 131(5):1561–1572.CrossRefPubMedGoogle Scholar
  39. 39.
    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(49):17216–17221.CrossRefPubMedGoogle Scholar
  40. 40.
    Harada N, Miyoshi H, Murai N et al. Lack of tumorigenesis in the mouse liver after adenovirus-mediated expression of a dominant stable mutant of beta-catenin. Cancer Res 2002; 62(7):1971–1977.PubMedGoogle Scholar
  41. 41.
    Harada N, Oshima H, Katoh M et al. Hepatocarcinogenesis in mice with beta-catenin and ha-ras gene mutations. Cancer Res 2004; 64(1):48–54.CrossRefPubMedGoogle Scholar
  42. 42.
    Li F, Xiang Y, Potter J et al. Conditional deletion of c-myc does not impair liver regeneration. Cancer Res 2006; 66(11):5608–5612.CrossRefPubMedGoogle Scholar
  43. 43.
    Pecina Slaus N, Pavelic K, Pavelic J. Loss of heterozygosity and protein expression of APC gene in renal cell carcinomas. J Mol Med 1999; 77(5):446–453.CrossRefPubMedGoogle Scholar
  44. 44.
    Kim YS, Kang YK, Kim JB et al. beta-catenin expression and mutational analysisin renal cell carcinomas. Pathol Int 2000; 50(9):725–730.CrossRefPubMedGoogle Scholar
  45. 45.
    Qian CN, Knol J, Igarashi P et al. Cystic renal neoplasia following conditional inactivation of apc in mouse renal tubular epithelium. J Biol Chern 2005; 280(5):3938–3945.CrossRefGoogle Scholar
  46. 46.
    Sansom OJ, Griffiths DF, Reed KR et al. Apc deficiency predisposes to renal carcinoma in the mouse. Oncogene 2005; 24(55):8205–8210.PubMedGoogle Scholar
  47. 47.
    Sansom OJ, Meniel V, Wilkins JA et al. Loss of apc allows phenotypic manifestation of the transforming properties of an endogenous K-ras oncogene in vivo. Proc Natl Acad Sci USA 2006; 103(38):14122–14127.CrossRefPubMedGoogle Scholar
  48. 48.
    Jin Z, Tamura G, Tsuchiya T et al. Adenomatous polyposis coli (APC) gene promoter hypermethylation in primary breast cancers. Br J Cancer 2001; 85(1):69–73.CrossRefPubMedGoogle Scholar
  49. 49.
    Virmani AK, Rathi A, Sathyanarayana UG et al. Aberrant methylation of the adenomatous polyposis coli (APC) gene promoter 1A in breast and lung carcinomas. Clin Cancer Res 2001; 7(7):1998–2004.PubMedGoogle Scholar
  50. 50.
    Selbert S, Bentley DJ, Melton DW et al. Efficient BLG-cre mediated gene deletion in the mammary gland. Transgenic Res 1998; 7(5):387–396.CrossRefPubMedGoogle Scholar
  51. 51.
    Gallagher RC, Hay T, Meniel V et al. Inactivation of apc perturbs mammary development, but only directly results in acanthoma in the context of Tcf-1 deficiency. Oncogene 2002; 21(42):6446–6457.CrossRefPubMedGoogle Scholar
  52. 52.
    Meniel V, Hay T, Douglas Jones A et al. Mutations in apc and p53 synergize to promote mammary neoplasia. Cancer Res 2005; 65(2):410–416.PubMedGoogle Scholar
  53. 53.
    Sansom OJ, Stark LA, Dunlop MG et al. Suppression of intestinal and mammary neoplasia by lifetime administration of aspirin in apc(Min/+) and apc(Min/+), Msh2(−/−) mice. Cancer Res 2001; 61(19):7060–7064.PubMedGoogle Scholar
  54. 54.
    Mahmoud NN, Boolbol SK, Dannenberg AJ et al. The sulfide metabolite of sulindac prevents tumors and restores enterocyte apoptosis in a murine model of familial adenomatous polyposis. Carcinogenesis 1998; 19(1):87–91.CrossRefPubMedGoogle Scholar
  55. 55.
    Mahmoud NN, Dannenberg AJ, Mestre J et al. Aspirin prevents tumors in a murine model of familial adenomatous polyposis. Surgery 1998; 124(2):225–231.PubMedGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2009

Authors and Affiliations

  1. 1.Beaton Institute of Cancer ResearchGlasgowUK

Personalised recommendations