Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Inactivation of the retinoblastoma gene yields a mouse model of malignant colorectal cancer

Oncogene volume 34, pages 5890–5899 (2015)Cite this article

Subjects

Abstract

The retinoblastoma gene (Rb) is mutated at significant frequency in various human epithelial tumors, including colorectal cancer, and is strongly associated with metastatic disease. However, sole inactivation of Rb in the mouse has so far failed to yield epithelial cancers. Here, we specifically inactivate Rb and/or p53 in the urogenital epithelium and the intestine. We find that the loss of both tumor suppressors is unable to yield tumors in the transitional epithelium lining the bladder, kidneys and ureters. Instead, these mice develop highly metastatic tumors of neuroendocrine, not epithelial, origin within the urogenital tract to give prostate cancer in the males and vaginal tumors in the females. Additionally, we discovered that the sole inactivation of Rb in the intestine was sufficient to induce formation of metastatic colorectal adenocarcinomas. These tumors closely mirror the human disease in regard to the age of onset, histological appearance, invasiveness and metastatic potential. Like most human colorectal carcinomas, our murine Rb-deficient tumors demonstrate genomic instability and they show activation of β-catenin. Deregulation of the Wnt/β-catenin pathway is specific to the intestinal tumors, as genomic instability but not activation of β-catenin was observed in the neuroendocrine tumors. To date, attempts to generate genetically engineered mouse models of colorectal cancer tumors have yielded mostly cancer of the small intestine, which rarely occurs in humans. Our system provides the opportunity to accurately model and study colorectal cancer in the mouse via a single gene mutation.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  1. Burkhart DL, Sage J . Cellular mechanisms of tumour suppression by the retinoblastoma gene. Nat Rev Cancer 2008; 8: 671–682.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Clarke AR, Maandag ER, van Roon M, van der Lugt NM, van der Valk M, Hooper ML et al. Requirement for a functional Rb-1 gene in murine development. Nature 1992; 359: 328–330.

    Article  CAS  PubMed  Google Scholar 

  3. Williams BO, Schmitt EM, Remington L, Bronson RT, Albert DM, Weinberg RA et al. Extensive contribution of Rb-deficient cells to adult chimeric mice with limited histopathological consequences. Embo J 1994; 13: 4251–4259.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Maandag EC, van der Valk M, Vlaar M, Feltkamp C, O'Brien J, van Roon M et al. Developmental rescue of an embryonic-lethal mutation in the retinoblastoma gene in chimeric mice. EMBO J 1994; 13: 4260–4268.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Henley SA, Dick FA . The retinoblastoma family of proteins and their regulatory functions in the mammalian cell division cycle. Cell Div 2012; 7: 10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Parisi T, Bronson RT, Lees JA . Inhibition of pituitary tumors in Rb mutant chimeras through E2f4 loss reveals a key suppressive role for the pRB/E2F pathway in urothelium and ganglionic carcinogenesis. Oncogene 2009; 28: 500–508.

    Article  CAS  PubMed  Google Scholar 

  7. Lee EY, Cam H, Ziebold U, Rayman JB, Lees JA, Dynlacht BD . E2F4 loss suppresses tumorigenesis in Rb mutant mice. Cancer Cell 2002; 2: 463–472.

    Article  CAS  PubMed  Google Scholar 

  8. Humbert PO, Rogers C, Ganiatsas S, Landsberg RL, Trimarchi JM, Dandapani S et al. E2F4 is essential for normal erythrocyte maturation and neonatal viability. Mol Cell 2000; 6: 281–291.

    Article  CAS  PubMed  Google Scholar 

  9. Wu XR . Urothelial tumorigenesis: a tale of divergent pathways. Nat Rev Cancer 2005; 5: 713–725.

    Article  CAS  PubMed  Google Scholar 

  10. Dinney CP, McConkey DJ, Millikan RE, Wu X, Bar-Eli M, Adam L et al. Focus on bladder cancer. Cancer Cell 2004; 6: 111–116.

    Article  CAS  PubMed  Google Scholar 

  11. Rosenberg JE, Hahn WC . Bladder cancer: modeling and translation. Genes Dev 2009; 23: 655–659.

    Article  CAS  PubMed  Google Scholar 

  12. He F, Mo L, Zheng XY, Hu C, Lepor H, Lee EY et al. Deficiency of pRb family proteins and p53 in invasive orothelial carcinogenesis. Cancer Res 2009; 69: 9413–9421.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Saam JR, Gordon JI . Inducible gene knockouts in the small intestinal and colonic epithelium. J Biol Chem 1999; 274: 38071–38082.

    Article  CAS  PubMed  Google Scholar 

  14. Lawrence MS, Stojanov P, Mermel CH, Robinson JT, Garraway LA, Golub TR et al. Discovery and saturation analysis of cancer genes across 21 tumour types. Nature 2014; 505: 495–501.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Zack TI, Schumacher SE, Carter SL, Cherniack AD, Saksena G, Tabak B et al. Pan-cancer patterns of somatic copy number alteration. Nat Genet 2013; 45: 1134–1140.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Yoo LI, Liu DW, Le Vu S, Bronson RT, Wu H, Yuan J . Pten deficiency activates distinct downstream signaling pathways in a tissue-specific manner. Cancer Res 2006; 66: 1929–1939.

    Article  CAS  PubMed  Google Scholar 

  17. Sharma A, Yeow WS, Ertel A, Coleman I, Clegg N, Thangavel C et al. The retinoblastoma tumor suppressor controls androgen signaling and human prostate cancer progression. J Clin Invest 2010; 120: 4478–4492.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Humphrey PA . Histological variants of prostatic carcinoma and their significance. Histopathology 2012; 60: 59–74.

    Article  PubMed  Google Scholar 

  19. Zhou Z, Flesken-Nikitin A, Corney DC, Wang W, Goodrich DW, Roy-Burman P et al. Synergy of p53 and Rb deficiency in a conditional mouse model for metastatic prostate cancer. Cancer Res 2006; 66: 7889–7898.

    Article  CAS  PubMed  Google Scholar 

  20. Haigis K, Sage J, Glickman J, Shafer S, Jacks T . The related retinoblastoma (pRb) and p130 proteins cooperate to regulate homeostasis in the intestinal epithelium. J Biol Chem 2006; 281: 638–647.

    Article  CAS  PubMed  Google Scholar 

  21. Kucherlapati MH, Nguyen AA, Bronson RT, Kucherlapati RS . Inactivation of conditional Rb by Villin-Cre leads to aggressive tumors outside the gastrointestinal tract. Cancer Res 2006; 66: 3576–3583.

    Article  CAS  PubMed  Google Scholar 

  22. Nandan MO, Yang VW . Genetic and chemical models of colorectal cancer in mice. Curr Colorectal Cancer Rep 2010; 6: 51–59.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Schwitalla S, Ziegler PK, Horst D, Becker V, Kerle I, Begus-Nahrmann Y et al. Loss of p53 in enterocytes generates an inflammatory microenvironment enabling invasion and lymph node metastasis of carcinogen-induced colorectal tumors. Cancer Cell 2013; 23: 93–106.

    Article  CAS  PubMed  Google Scholar 

  24. Markowitz SD, Bertagnolli MM . Molecular origins of cancer: Molecular basis of colorectal cancer. N Engl J Med 2009; 361: 2449–2460.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Moran A, Ortega P, de Juan C, Fernandez-Marcelo T, Frias C, Sanchez-Pernaute A et al. Differential colorectal carcinogenesis: Molecular basis and clinical relevance. World J Gastrointest Oncol 2010; 2: 151–158.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Coschi CH, Martens AL, Ritchie K, Francis SM, Chakrabarti S, Berube NG et al. Mitotic chromosome condensation mediated by the retinoblastoma protein is tumor-suppressive. Genes Dev 2010; 24: 1351–1363.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Manning AL, Longworth MS, Dyson NJ . Loss of pRB causes centromere dysfunction and chromosomal instability. Genes Dev 2010; 24: 1364–1376.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Manning AL, Yazinski SA, Nicolay B, Bryll A, Zou L, Dyson NJ . Suppression of genome instability in pRB-deficient cells by enhancement of chromosome cohesion. Mol Cell 2014; 53: 993–1004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Burgess AW, Faux MC, Layton MJ, Ramsay RG . Wnt signaling and colon tumorigenesis—a view from the periphery. Exp Cell Res 2011; 317: 2748–2758.

    Article  CAS  PubMed  Google Scholar 

  30. Horst D, Reu S, Kriegl L, Engel J, Kirchner T, Jung A . The intratumoral distribution of nuclear beta-catenin is a prognostic marker in colon cancer. Cancer 2009; 115: 2063–2070.

    Article  PubMed  Google Scholar 

  31. Blache P, van de Wetering M, Duluc I, Domon C, Berta P, Freund JN et al. SOX9 is an intestine crypt transcription factor, is regulated by the Wnt pathway, and represses the CDX2 and MUC2 genes. J Cell Biol 2004; 166: 37–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Zhang ZT, Pak J, Shapiro E, Sun TT, Wu XR . Urothelium-specific expression of an oncogene in transgenic mice induced the formation of carcinoma in situ and invasive transitional cell carcinoma. Cancer Res 1999; 59: 3512–3517.

    CAS  PubMed  Google Scholar 

  33. Terry S, Beltran H . The many faces of neuroendocrine differentiation in prostate cancer progression. Front Oncol 2014; 4: 60.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Aparicio A, Den RB, Knudsen KE . Time to stratify? The retinoblastoma protein in castrate-resistant prostate cancer. Nat Rev Urol 2011; 8: 562–568.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kaplan-Lefko PJ, Chen TM, Ittmann MM, Barrios RJ, Ayala GE, Huss WJ et al. Pathobiology of autochthonous prostate cancer in a pre-clinical transgenic mouse model. Prostate 2003; 55: 219–237.

    Article  PubMed  Google Scholar 

  36. Zeineldin M, Neufeld KL . Understanding phenotypic variation in rodent models with germline Apc mutations. Cancer Res 2013; 73: 2389–2399.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Johnson RL, Fleet JC . Animal models of colorectal cancer. Cancer Metastasis Rev 2012; 32: 39–61.

    Article  Google Scholar 

  38. Hung KE, Maricevich MA, Richard LG, Chen WY, Richardson MP, Kunin A et al. Development of a mouse model for sporadic and metastatic colon tumors and its use in assessing drug treatment. Proc Natl Acad Sci USA 2010; 107: 1565–1570.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Yang HS, Hinds PW . pRb-mediated control of epithelial cell proliferation and Indian hedgehog expression in mouse intestinal development. BMC Dev Biol 2007; 7: 6.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Kucherlapati MH, Yang K, Fan K, Kuraguchi M, Sonkin D, Rosulek A et al. Loss of Rb1 in the gastrointestinal tract of Apc1638N mice promotes tumors of the cecum and proximal colon. Proc Natl Acad Sci USA 2008; 105: 15493–15498.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Gope R, Christensen MA, Thorson A, Lynch HT, Smyrk T, Hodgson C et al. Increased expression of the retinoblastoma gene in human colorectal carcinomas relative to normal colonic mucosa. J Natl Cancer Inst 1990; 82: 310–314.

    Article  CAS  PubMed  Google Scholar 

  42. Morris EJ, Ji JY, Yang F, Di Stefano L, Herr A, Moon NS et al. E2F1 represses beta-catenin transcription and is antagonized by both pRB and CDK8. Nature 2008; 455: 552–556.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Sage J, Miller AL, Perez-Mancera PA, Wysocki JM, Jacks T . Acute mutation of retinoblastoma gene function is sufficient for cell cycle re-entry. Nature 2003; 424: 223–228.

    Article  CAS  PubMed  Google Scholar 

  44. Jonkers J, Meuwissen R, van der Gulden H, Peterse H, van der Valk M, Berns A . Synergistic tumor suppressor activity of BRCA2 and p53 in a conditional mouse model for breast cancer. Nat Genet 2001; 29: 418–425.

    Article  CAS  PubMed  Google Scholar 

  45. Parisi T, Yuan TL, Faust AM, Caron AM, Bronson R, Lees JA . Selective requirements for E2f3 in the development and tumorigenicity of Rb-deficient chimeric tissues. Mol Cell Biol 2007; 27: 2283–2293.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We are indebted to Omer Yilmaz for scientific suggestions and professional evaluation of the pathology slides, Kevin Haigis for unpublished information and reagents, A. Amsterdam and S. Frank for critical reading of the manuscript, and the Koch Institute Swanson Biotechnology Center for technical support, particularly the Histology Core. This work was supported by NIH/NCI grants to the Koch Institute (P30-CA14051), and to JAL (P01-CA42063 and RO1-CA121921), a Ludwig Scholar at MIT.

Author information

Authors and Affiliations

  1. Koch Institute for Integrative Cancer Research, Cambridge, MA, USA

    T Parisi & J A Lees

  2. Department of Pathology, Tufts Cummings School of Veterinary Medicine, North Grafton, MA, USA

    R T Bronson

  3. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA

    J A Lees

Authors
  1. T Parisi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. R T Bronson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J A Lees
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J A Lees.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Parisi, T., Bronson, R. & Lees, J. Inactivation of the retinoblastoma gene yields a mouse model of malignant colorectal cancer. Oncogene 34, 5890–5899 (2015). https://doi.org/10.1038/onc.2015.30

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2015.30

This article is cited by

Search

Advanced search

Quick links