Journal of Gastrointestinal Surgery

, Volume 12, Issue 8, pp 1452–1458

Targeted Suppression of β-Catenin Blocks Intestinal Adenoma Formation in APC Min Mice

  • Paul J. Foley
  • Randall P. Scheri
  • Christopher J. Smolock
  • James Pippin
  • Douglas W. Green
  • Jeffrey A. Drebin
original article



Mutations involving the adenomatous polyposis coli (APC) tumor suppressor gene leading to activation of β-catenin have been identified in the majority of sporadic colonic adenocarcinomas and in essentially all colonic tumors from patients with Familial Adenomatous Polyposis. The C57BL/6J-APCmin (Min) mouse, which carries a germ line mutation in the murine homolog of the APC gene is a useful model for intestinal adenoma formation linked to loss of APC activity. One of the critical downstream molecules regulated by APC is β-catenin; molecular targeting of β-catenin is, thus, an attractive chemopreventative strategy in colon cancer. Antisense oligodeoxynucleotides (AODNs) capable of downregulating murine β-catenin have been identified.

Analysis of β-catenin Protein Expression in Liver Tissue and Intestinal Adenomas

Adenomas harvested from mice treated for 7 days with β-catenin AODNs demonstrated clear downregulation of β-catenin expression, which was accompanied by a significant reduction in proliferation. There was no effect on proliferation in normal intestinal epithelium. Min mice treated systemically with β-catenin AODNs over a 6-week period had a statistically significant reduction in the number of intestinal adenomas. These studies provide direct evidence that targeted suppression of β-catenin inhibits the formation of intestinal adenomas in APC-mutant mice. Furthermore, these studies suggest that molecular targeting of β-catenin holds significant promise as a chemopreventative strategy in colon cancer.


Beta-catenin Adenoma Colon cancer Chemoprevention 


  1. 1.
    American Cancer Society. Cancer Facts and Figures 2007. Atlanta: American Cancer Society, 2007.Google Scholar
  2. 2.
    Potter J. Colorectal cancer: molecules and populations. J Natl Cancer Inst 1999;91:916–932.PubMedCrossRefGoogle Scholar
  3. 3.
    Cadigan K, Nusse R. Wnt signaling: a common theme in animal development. Genes Dev 1997;11:3286–3305.PubMedCrossRefGoogle Scholar
  4. 4.
    Novak A, Dedhar S. Signaling through b-catenin and Lef/Tcf. Cell Mol Life Sci 1999;56:523–537.PubMedCrossRefGoogle Scholar
  5. 5.
    van de Wetering M, Sancho E, Verweij C, de Lau W, Oving I, Hurlstone A, van der Horn K, Batlle E, Coudreuse D, Haramis A, Tjon-Pon-Fong M, Moerer P, van den Born M, Soete G, Pals S, Eilers M, Medema R, Clevers H. The b-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells. Cell 2002;111:241–250.PubMedCrossRefGoogle Scholar
  6. 6.
    Alexander N, Wong C, Pignatelli M. b-Catenin-A linchpin in colorectal carcinogenesis. Am J Pathol 2002;160:389–401.Google Scholar
  7. 7.
    He T, Sparks A, Rago C, Hermeking H, Zawel L, da Costa L, Morin P, Vogelstein B, Kinzler K. Identification of c-myc as a target of the APC pathway. Science 1998;281:1509–1512.PubMedCrossRefGoogle Scholar
  8. 8.
    Tetsu O, McCormick F. b-Catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature 1999;398:422–426.PubMedCrossRefGoogle Scholar
  9. 9.
    Mann B, Gelos M, Siedow A, Hanski M, Gratchev A, Ilyas M, Bodmer W, Moyer M, Rieken E, Buhr H, Hanski C. Target genes of b-catenin-T cell-factor/lymphoid-enhancer-factor signaling in human colorectal carcinomas. Proc Natl Acad Sci U S A 1999;96:1603–1608.PubMedCrossRefGoogle Scholar
  10. 10.
    Lin Y, Ono K, Satoh S, Ishiguro H, Fujita M, Miwa N, Tanaka T, Tsunoda T, Yang K, Nakamura Y, Furukawa Y. Identification of AF17 as a downstream gene of the b-catenin/T-cell factor pathway and its involvement in colorectal carcinogenesis. Cancer Res 2001;61:6345–6349.PubMedGoogle Scholar
  11. 11.
    He T, Chan T, Vogelstein B, Kinzler K. PPARd is an APC-regulated target of nonsteroidal anti-inflammatory drug. Cell 1999;99:335–345.PubMedCrossRefGoogle Scholar
  12. 12.
    Powell S, Zilz N, Beazer-Barklay T, Bryan T, Hamilton S, Thibodeau S, Vogelstein B, Kinzler K. APC mutations occur early during colorectal tumorigenesis. Nature 1992;359:235–237.PubMedCrossRefGoogle Scholar
  13. 13.
    Fodde R, Smits R, Clevers H. APC, signal transduction and genetic instability in colorectal cancer. Nat Rev Cancer 2001;1:55–67.PubMedCrossRefGoogle Scholar
  14. 14.
    Kinzler K, Vogelstein B. Lessons from hereditary colorectal cancer. Cell 1996;87:159–170.PubMedCrossRefGoogle Scholar
  15. 15.
    Sparks A, Morin P, Vogelstein B, Kinzler K. Mutational analysis of the APC/beta-catenin/TCF pathway in colorectal cancer. Cancer Res 1998;58:1130–1134.PubMedGoogle Scholar
  16. 16.
    Kinzler K, Nilbert M, Su L, Vogelstein B, Bryan T, Levy D, Smith K, Preisinger A, Hedge P, McKechnie D, Finniear R, Markham A. Identification of FAP locus genes from chromosome 5q21. Science 1991;253:661–665.PubMedCrossRefGoogle Scholar
  17. 17.
    Nishisho I, Nakamura Y, Miyoshi Y, Miki Y, Ando H, Horii A, Koyama K, Utsonomiya J, Baba S, Hedge P. Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. Science 1991;253:665–669.PubMedCrossRefGoogle Scholar
  18. 18.
    Lynch H, de la Chapelle A. Hereditary colorectal cancer. N Engl J Med 2003;348:919–932.PubMedCrossRefGoogle Scholar
  19. 19.
    Su L, Kinzler K, Vogelstein B, Preisinger A, Moser A, Luongo C, Gould K, Dove W. Multiple intestinal neoplasia caused by a mutation in the murine homolog of the APC gene. Science 1991;256:668–670.CrossRefGoogle Scholar
  20. 20.
    Roh H, Green D, Boswell C, Pippin J, Drebin J. Suppression of b-catenin inhibits the neoplastic growth of APC-mutant colon cancer cells. Cancer Res 2001;61:6563–6568.PubMedGoogle Scholar
  21. 21.
    Green D, Roh H, Pippin J, Drebin J. b-Catenin antisense treatment decreases β-catenin expression and tumor growth rate in colon carcinoma xenografts. J Surg Res 2001;101:16–20.PubMedCrossRefGoogle Scholar
  22. 22.
    Verma U, Surabhi R, Schmaltieg A, Becerra C, Gaynor R. Small interfering RNAs directed against b-catenin inhibit the in vitro and in vivo growth of colon cancer cells. Clin Cancer Res 2003;9:1291–1300.PubMedGoogle Scholar
  23. 23.
    Corpet D, Pierre F. Point: from animal models to prevention of colon cancer. Systematic review of chemoprevention in min mice and choice of the model system. Cancer Epidemiol Biomarkers Prev 2003;12:391–400.PubMedGoogle Scholar
  24. 24.
    McEntee M, Chiu C-H, Whelan J. Relationship of b-catenin and bcl-2 expression to sulindac-induced regression of intestinal tumors in min mice. Carcinogenesis 1999;20:635–640.PubMedCrossRefGoogle Scholar
  25. 25.
    Oikannen S, Pajari A, Mutanen M. Chemopreventive activity of hydroksymatairesinol in adenomatous polyposis colimultiple intestinal neoplasia (APC)min mice. Cancer Letters 2000;159:183–187.PubMedCrossRefGoogle Scholar
  26. 26.
    Oshima M, Murai N, Kargman S, Arguello M, Luk P, Kwong E, Taketo M, Evans J. Chemoprevention of intestinal polyposis in the APCD716 mouse by rofecoxib, a specific cyclooxygenase-2 inhibitor. Cancer Res 2001;61:1733–1740.PubMedGoogle Scholar
  27. 27.
    Schmelz E, Roberts P, Kustin E, Lemonnier L, Sullards C, Dillehay D, Merrill A. Modulation of intracellular b-catenin localization and intestinal tumorigenesis in vivo and in vitro by sphingolipids. Cancer Res 2001;61:6723–6729.PubMedGoogle Scholar
  28. 28.
    Williams J, Nath N, Chen J, Hundley T, Gao J, Kopelovich L, Kashfi K, Rigas B. Growth inhibition of human colon cancer cells by nitric oxide (NO)-donating aspirin is associated with cyclooxygenase-2 induction and b-catenin/T-cell factor signaling, nuclear factor-κB, and NO synthase 2 inhibition: implications for chemoprevention. Cancer Res 2003;63:7613–7618.PubMedGoogle Scholar
  29. 29.
    Orner G, Dashwood W, Blum C, Diaz D, Li Q, Dashwood R. Suppression of tumorigenesis in the APC min mouse: downregulation of b-catenin signaling by a combination of tea plus sulindac. Carcinogenesis 2003;24:263–267.PubMedCrossRefGoogle Scholar
  30. 30.
    Boon E, Keller J, Wormhoudt T, Giardiello G, Offerhaus G, van der Neut R, Pals S. Sulindac targets nuclear b-catenin accumulation and Wnt signaling in adenomas of patients with familial adenomatous polyposis in human colorectal cancer cell lines. Br J Cancer 2004;90:224–229.PubMedCrossRefGoogle Scholar
  31. 31.
    Dihlmann S, von Knebel Doeberitz M. Wnt/b-catenin-pathway as a molecular target for future anti-cancer therapeutics. Int J Cancer 2005;113:515–524.PubMedCrossRefGoogle Scholar
  32. 32.
    Kashfi K, Rigas B. Non-cox-2 targets and cancer: expanding the molecular target repertoire of chemoprevention. Biochem Pharmacol 2005;70:969–986.PubMedCrossRefGoogle Scholar

Copyright information

© The Society for Surgery of the Alimentary Tract 2008

Authors and Affiliations

  • Paul J. Foley
    • 1
  • Randall P. Scheri
    • 2
  • Christopher J. Smolock
    • 1
  • James Pippin
    • 1
  • Douglas W. Green
    • 1
    • 2
  • Jeffrey A. Drebin
    • 1
  1. 1.Department of SurgeryUniversity of Pennsylvania School of MedicinePhiladelphiaUSA
  2. 2.Department of SurgeryDuke University School of MedicineDurhamUSA

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