Gastroenterology
Volume 136, Issue 5 , Pages 1680-1688.e7 , May 2009

TGF-β Receptor Inactivation and Mutant Kras Induce Intestinal Neoplasms in Mice via a β-Catenin-Independent Pathway

  • Patty Trobridge

      Affiliations

    • Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
    • ,
  • Sue Knoblaugh

      Affiliations

    • Experimental Histopathology, Fred Hutchinson Cancer Research Center, Seattle, Washington
    • ,
  • M. Kay Washington

      Affiliations

    • Department of Pathology, Vanderbilt University School of Medicine, Nashville, Tennessee
    • ,
  • Nina M. Munoz

      Affiliations

    • Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
    • ,
  • Karen D. Tsuchiya

      Affiliations

    • Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
    • Department of Laboratory Medicine, University of Washington Medical School, Seattle, Washington
    • Department of Laboratories, Seattle Children's Hospital, Seattle, Washington
    • ,
  • Andres Rojas

      Affiliations

    • Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
    • Cancer Biology Department, Nashville, Tennessee
    • ,
  • Xiaoling Song

      Affiliations

    • Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
    • ,
  • Cornelia M. Ulrich

      Affiliations

    • Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
    • ,
  • Takehiko Sasazuki

      Affiliations

    • Department of Cell Biology, School of Medicine Fukuoka University, Fukuoka, Japan
    • ,
  • Senji Shirasawa

      Affiliations

    • Department of Cell Biology, School of Medicine Fukuoka University, Fukuoka, Japan
    • ,
  • William M. Grady

      Affiliations

    • Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
    • Department of Veterans Affairs R&D Service, Puget Sound Healthcare System, Seattle, Washington
    • Department of Medicine, University of Washington Medical School, Seattle, Washington
    • Corresponding Author InformationReprint requests Address requests for reprints to: William M. Grady, MD, Fred Hutchinson Cancer Research Center, Clinical Research Division, 1100 Fairview Ave N, D4-100, Seattle, Washington 98109. fax: (206) 667-2917

Received 5 August 2008 ,Accepted 29 January 2009.

References 

  1. Suzuki H, Watkins DN, Jair KW, et al. Epigenetic inactivation of SFRP genes allows constitutive WNT signaling in colorectal cancer. Nat Genet. 2004;36:417–422
  2. Grady WM, Markowitz SD. Genetic and epigenetic alterations in colon cancer. Ann Rev Genomics Hum Genet. 2002;3:101–128
  3. Parsons DW, Wang TL, Samuels Y, et al. Colorectal cancer: mutations in a signalling pathway. Nature. 2005;436:792
  4. Grady WM, Rajput A, Myeroff L, et al. Mutation of the type II transforming growth factor-β receptor is coincident with the transformation of human colon adenomas to malignant carcinomas. Cancer Res. 1998;58:3101–3104
  5. Munoz N, Upton M, Rojas A, et al. Transforming growth factor β receptor type II inactivation induces transformation of intestinal neoplasms initiated by Apc mutation. Cancer Res. 2006;66:9837–9844
  6. Haigis KM, Kendall KR, Wang Y, et al. Differential effects of oncogenic K-Ras and N-Ras on proliferation, differentiation and tumor progression in the colon. Nat Genet. 2008;40:600–608
  7. 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 U S A. 2006;103:14122–14127
  8. Biswas S, Chytil A, Washington K, et al. Transforming growth factor b receptor type ii inactivation promotes the establishment and progression of colon cancer. Cancer Res. 2004;64:4687–4692
  9. Ijichi H, Chytil A, Gorska AE, et al. Aggressive pancreatic ductal adenocarcinoma in mice caused by pancreas-specific blockade of transforming growth factor-β signaling in cooperation with active Kras expression. Genes Dev. 2006;20:3147–3160
  10. Grady WM, Myeroff LL, Swinler SE, et al. Mutational inactivation of transforming growth factor-β receptor type II in microsatellite stable colon cancers. Cancer Res. 1999;59:320–324
  11. Bierie B, Moses HL. TGF-β and cancer. Cytokine Growth Factor Rev. 2006;17:29–40
  12. Attisano L, Labbe E. TGF-β and Wnt pathway cross-talk. Cancer Metastasis Rev. 2004;23:53–61
  13. Massague J, Blain SW, Lo RS. TGF-β signaling in growth control, cancer, and heritable disorders. Cell. 2000;103:295–309
  14. Chytil A, Magnuson M, Wrigth C, et al. Conditional inactivation of the TGF-b type II receptor using Cre:Lox. Genesis. 2002;32:73–75
  15. Madison BB, Dunbar L, Qiao XT, et al. cis Elements of the Villin gene control expression in restricted domains of the vertical (crypt) and horizontal (duodenum, cecum) axes of the intestine. J Biol Chem. 2002;277:33275–33283
  16. Jackson EL, Willis N, Mercer K, et al. Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras. Genes Dev. 2001;15:3243–3248
  17. Markowitz S, Roberts A. Tumor supressor activity of the TGF-β pathway in human cancers. Cytokine Growth Factor Rev. 1996;7:93–102
  18. Shirasawa S, Furuse M, Yokoyama N, et al. Altered growth of human colon cancer cell lines disrupted at activated Ki-ras. Science. 1993;260:85–88
  19. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57–70
  20. Collado M, Gil J, Efeyan A, et al. Tumour biology: senescence in premalignant tumours. Nature. 2005;436:642
  21. Glick AB, Weinberg WC, Wu IH, et al. Transforming growth factor β 1 suppresses genomic instability independent of a G1 arrest, p53, and Rb. (published erratum appears in Cancer Res 1997;57:2079) Cancer Res. 1996;56:3645–3650
  22. Glick A, Popescu N, Alexander V, et al. Defects in transforming growth factor-β signaling cooperate with a Ras oncogene to cause rapid aneuploidy and malignant transformation of mouse keratinocytes. Proc Natl Acad Sci U S A. 1999;96:14949–14954
  23. Bruder CE, Piotrowski A, Gijsbers AA, et al. Phenotypically concordant and discordant monozygotic twins display different DNA copy-number-variation profiles. Am J Hum Genet. 2008;82:763–771
  24. Grady WM, Parkin RK, Mitchell PS, et al. Epigenetic silencing of the intronic microRNA hsa-miR-342 and its host gene EVL in colorectal cancer. Oncogene. 2008;27:3880–3888
  25. Lee D, Pearsall RS, Das S, et al. Epiregulin is not essential for development of intestinal tumors but is required for protection from intestinal damage. Mol Cell Biol. 2004;24:8907–8916
  26. Boon K, Osorio EC, Greenhut SF, et al. An anatomy of normal and malignant gene expression. Proc Natl Acad Sci U S A. 2002;99:11287–11292
  27. Biswas S, Trobridge P, Romero-Gallo J, et al. Mutational inactivation of TGFBR2 in microsatellite unstable colon cancer arises from the cooperation of genomic instability and the clonal outgrowth of transforming growth factor β resistant cells. Genes Chromosomes Cancer. 2008;47:95–106
  28. Tuveson DA, Shaw AT, Willis NA, et al. Endogenous oncogenic K-ras (G12D) stimulates proliferation and widespread neoplastic and developmental defects. Cancer Cell. 2004;5:375–387
  29. Calcagno SR, Li S, Colon M, et al. Oncogenic K-ras promotes early carcinogenesis in the mouse proximal colon. Int J Cancer. 2008;122:2462–2470
  30. Malumbres M, Barbacid M. To cycle or not to cycle: a critical decision in cancer. Nat Rev Cancer. 2001;1:222–231
  31. Ortega S, Malumbres M, Barbacid M. Cyclin D-dependent kinases, INK4 inhibitors and cancer. Biochim Biophys Acta. 2002;1602:73–87
  32. Bhowmick NA, Chytil A, Plieth D, et al. TGF-β signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia. Science. 2004;303:848–851
  33. Letterio JJ. TGF-β signaling in T cells: roles in lymphoid and epithelial neoplasia. Oncogene. 2005;24:5701–5712
  34. Bhowmick NA, Ghiassi M, Bakin A, et al. Transforming growth factor-b1 mediates epithelial to mesenchymal transdifferentiation through a RhoA-dependent mechanism. Mol Biol Cell. 2001;12:27–36
  35. Janssen KP, Alberici P, Fsihi H, et al. APC and oncogenic KRAS are synergistic in enhancing Wnt signaling in intestinal tumor formation and progression. Gastroenterology. 2006;131:1096–1109
  36. Baba I, Shirasawa S, Iwamoto R, et al. Involvement of deregulated epiregulin expression in tumorigenesis in vivo through activated Ki-Ras signaling pathway in human colon cancer cells. Cancer Res. 2000;60:6886–6889
  37. Khambata-Ford S, Garrett CR, Meropol NJ, et al. Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab. J Clin Oncol. 2007;25:3230–3237

 Conflicts of interest The authors disclose no conflicts.

 Funding Supported by NCI RO1CA115513, Presidential Early Career Award for Scientists and Engineers (R&D Service, Department of Veterans Affairs; to W.M.G.), and 5 P30 CA015704.

PII: S0016-5085(09)00170-X

doi: 10.1053/j.gastro.2009.01.066

Gastroenterology
Volume 136, Issue 5 , Pages 1680-1688.e7 , May 2009

Article Tools

* Image Usage & Resolution