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.

Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis

Nature volume 425, pages 851–856 (2003)Cite this article

Abstract

Hedgehog signalling—an essential pathway during embryonic pancreatic development, the misregulation of which has been implicated in several forms of cancer—may also be an important mediator in human pancreatic carcinoma1,2,3,4,5,6,7,8. Here we report that sonic hedgehog, a secreted hedgehog ligand, is abnormally expressed in pancreatic adenocarcinoma and its precursor lesions: pancreatic intraepithelial neoplasia (PanIN). Pancreata of Pdx–Shh mice (in which Shh is misexpressed in the pancreatic endoderm) develop abnormal tubular structures, a phenocopy of human PanIN-1 and -2. Moreover, these PanIN-like lesions also contain mutations in K-ras and overexpress HER-2/neu, which are genetic mutations found early in the progression of human pancreatic cancer. Furthermore, hedgehog signalling remains active in cell lines established from primary and metastatic pancreatic adenocarcinomas. Notably, inhibition of hedgehog signalling by cyclopamine induced apoptosis and blocked proliferation in a subset of the pancreatic cancer cell lines both in vitro and in vivo. These data suggest that this pathway may have an early and critical role in the genesis of this cancer, and that maintenance of hedgehog signalling is important for aberrant proliferation and tumorigenesis.

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

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

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

Figure 1: Immunohistochemical identification of SHH.
Figure 2: Histological comparison of human PanINs and Pdx–Shh mouse pancreata.
Figure 3: Hedgehog signalling pathway.
Figure 4: Effects of cyclopamine treatment on pancreatic adenocarcinoma cells.
Figure 5: Cyclopamine treatment blocks tumour formation of human pancreatic adenocarcinoma cells after transplantation into nude mice.

References

  1. Capdevila, J., Estrada, M. P., Sanchez-Herrero, E. & Guerrero, I. The Drosophila segment polarity gene patched interacts with decapentaplegic in wing development. EMBO J. 13, 71–82 (1994)

    Article  CAS  Google Scholar 

  2. Hardcastle, Z., Mo, R., Hui, C.-C. & Sharpe, P. T. The Shh signalling pathway in tooth development: defects in Gli2 and Gli3 mutants. Development 125, 2803–2811 (1998)

    CAS  PubMed  Google Scholar 

  3. Marigo, V. & Tabin, C. Regulation of patched by sonic hedgehog in the developing neural tube. Proc. Natl Acad. Sci. USA 93, 9346–9351 (1996)

    Article  ADS  CAS  Google Scholar 

  4. Riddle, R. D., Johnson, R. L., Laufer, E. & Tabin, C. Sonic hedgehog mediates the polarizing activity of the ZPA. Cell 75, 1401–1416 (1993)

    Article  CAS  Google Scholar 

  5. St-Jacques, B. et al. Sonic hedgehog signaling is essential for hair development. Curr. Biol. 8, 1058–1068 (1998)

    Article  CAS  Google Scholar 

  6. Roberts, D. J. in Development of the Gastrointestinal Tract (eds Sanderson, I. R. & Walker, W. A.) 1–12 (Decker, Hamilton, Ontario, 2000)

    Google Scholar 

  7. Hebrok, M. Hedgehog signaling in pancreas development. Mech. Dev. 120, 45–47 (2003)

    Article  CAS  Google Scholar 

  8. Watkins, D. N. et al. Hedgehog signaling within airway epithelial progenitors and in small-cell lung cancer. Nature 422, 313–317 (2003)

    Article  ADS  CAS  Google Scholar 

  9. van den Brink, G. R. et al. Sonic hedgehog regulates gastric gland morphogenesis in man and mouse. Gastroenterology 121, 317–328 (2001)

    Article  CAS  Google Scholar 

  10. Johnson, R. L. et al. Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science 272, 1668–1671 (1996)

    Article  ADS  CAS  Google Scholar 

  11. Wicking, C., Smyth, I. & Bale, A. The hedgehog signalling pathway in tumorigenesis and development. Oncogene 18, 7844–7851 (1999)

    Article  CAS  Google Scholar 

  12. Hruban, R. et al. Pancreatic intraepithelial neoplasia. Am. J. Surg. Pathol. 25, 579–586 (2001)

    Article  CAS  Google Scholar 

  13. Wilentz, R. E. et al. Loss of expression of Dpc4 in pancreatic epithelial neoplasia: evidence that DPC4 inactivation occurs late in neoplastic progression. Cancer Res. 60, 2002–2006 (2000)

    CAS  PubMed  Google Scholar 

  14. Day, J. D. et al. Immunohistochemical evaluation of HER-2/neu oncogene expression in pancreatic adenocarcinoma and pancreatic intraepithelial neoplasms. Hum. Pathol. 27, 119–124 (1996)

    Article  CAS  Google Scholar 

  15. Wilentz, R. E. et al. Inactivation of the p16 (INK4A) tumor-suppressor gene in pancreatic duct lesions: loss of intranuclear expression. Cancer Res. 58, 4740–4744 (1998)

    CAS  PubMed  Google Scholar 

  16. Hebrok, M., Kim, S. K., St-Jacques, B., McMahon, A. P. & Melton, D. A. Regulation of pancreas development by hedgehog signaling. Development 127, 4905–4913 (2000)

    CAS  PubMed  Google Scholar 

  17. Jaffee, E. M. et al. Development and characterization of a cytokine-secreting pancreatic adenocarcinoma vaccine from primary tumors for use in clinical trials. Cancer J. Sci. Am. 4, 194–203 (1998)

    CAS  PubMed  Google Scholar 

  18. Taipale, J. et al. Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine. Nature 406, 1005–1009 (2000)

    Article  ADS  CAS  Google Scholar 

  19. Berman, D. M. et al. Medulloblastoma growth inhibition by hedgehog pathway blockade. Science 297, 1559–1561 (2002)

    Article  ADS  MathSciNet  CAS  Google Scholar 

  20. Incardona, J. P., Gaffield, W., Kapur, R. P. & Roelink, H. The teratogenic Veratrum alkaloid cyclopamine inhibits sonic hedgehog signal transduction. Development 125, 3553–3562 (1998)

    CAS  Google Scholar 

  21. Sasaki, H., Hui, C., Nakafuku, M. & Kondoh, H. A binding site for Gli proteins is essential for HNF-3 beta floor plate enhancer activity in transgenics and can respond to Shh in vitro. Development 124, 1313–1322 (1997)

    CAS  PubMed  Google Scholar 

  22. Lee, J., Platt, K. A., Censullo, P. & Ruiz I Altaba, A. Gli1 is a target of Sonic hedgehog that induces ventral neural tube development. Development 124, 2537–2552 (1997)

    CAS  PubMed  Google Scholar 

  23. Hebrok, M., Kim, S. K. & Melton, D. A. Notochord repression of endodermal Sonic hedgehog permits pancreas development. Genes Dev. 12, 1705–1713 (1998)

    Article  CAS  Google Scholar 

  24. Roberts, D. J., Smith, D. M., Goff, D. & Tabin, C. Epithelial-mesenchymal signaling during the regionalization of the chick gut. Development 125, 2791–2801 (1998)

    CAS  Google Scholar 

  25. Ramalho-Santos, M., Melton, D. A. & McMahon, A. P. Hedgehog signals regulate multiple aspects of gastrointestinal development. Development 127, 2763–2772 (2000)

    CAS  PubMed  Google Scholar 

  26. Apelqvist, A., Ahlegren, U. & Edlund, H. Sonic hedgehog directs specialised mesoderm differentiation in the intestine and pancreas. Curr. Biol. 7, 801–804 (1997)

    Article  CAS  Google Scholar 

  27. Hasegawa, Y. et al. Detection of K-ras mutations in DNAs isolated from feces of patients with colorectal tumors by mutant-allele-specific amplification (MASA). Oncogene 10, 1441–1445 (1995)

    CAS  PubMed  Google Scholar 

  28. Ito, Y. et al. Frequent detection of K-ras mutation in stool samples of colorectal carcinoma patients after improved DNA extraction: Comparison with tissue samples. Int. J. Oncol. 20, 1263–1268 (2002)

    CAS  PubMed  Google Scholar 

  29. Lopez, T. & Hanahan, D. Elevated levels of IGF-1 receptor convey invasive and metastatic capability in a mouse model of pancreatic islet tumorigenesis. Cancer Cell 1, 339–353 (2002)

    Article  CAS  Google Scholar 

  30. Sander, M. et al. Genetic analysis reveals that PAX6 is required for normal transcription of pancreatic hormone genes and islet development. Genes Dev. 11, 1662–1673 (1997)

    Article  CAS  Google Scholar 

  31. Berman, D. M. et al. Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours. Nature doi:10.1038/nature01972 (this issue)

Download references

Acknowledgements

S.P.T. and co-workers are grateful to D. A. Melton and P. A. Donahoe for discussion and review of the manuscript; H. Edlund for supplying the construct and initial pancreatic tissue for the Pdx–Shh transgenic mouse; and C. Tabin for the Shh in situ probe. We also thank N. Frost for editorial assistance. This work was supported in part by a grant from the Lustgarten Foundation to S.P.T. M.H. and co-workers thank C. Basbaum, D. Hanahan, I. Herskowitz, T. Kornberg, M. Tempero and members of the Hebrok laboratory for discussions and comments on the manuscript. We thank L. Jaffee for provision of the Panc series of cells. We are grateful to L. Spector for editorial assistance. This work was supported by grants to M.H. from the Juvenile Diabetes Foundation and the National Institutes of Health.

Authors' contributions S.P.T. and M.H. are senior authors.

Author information

Author notes

  1. Sarah P. Thayer and Marina Pasca di Magliano: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, 02114, USA

    Sarah P. Thayer, Corinne M. Nielsen, Carlos Fernández-del Castillo, Bozena Antoniu & Andrew L. Warshaw

  2. Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, 02114, USA

    Corinne M. Nielsen, Drucilla J. Roberts & Gregory Y. Lauwers

  3. Gastroenterology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, 02114, USA

    Vijay Yajnik

  4. Diabetes Center, Department of Medicine, University of California, San Francisco, California, 94143, USA

    Marina Pasca di Magliano, Patrick W. Heiser, Yan Ping Qi & Matthias Hebrok

  5. Cancer Research Institute, University of California, San Francisco, California, 94143, USA

    Stephan Gysin & Martin McMahon

Authors
  1. Sarah P. Thayer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marina Pasca di Magliano
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Patrick W. Heiser
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Corinne M. Nielsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Drucilla J. Roberts
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Gregory Y. Lauwers
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yan Ping Qi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Stephan Gysin
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Carlos Fernández-del Castillo
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Vijay Yajnik
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Bozena Antoniu
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Martin McMahon
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Andrew L. Warshaw
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Matthias Hebrok
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Sarah P. Thayer or Matthias Hebrok.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Thayer, S., di Magliano, M., Heiser, P. et al. Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature 425, 851–856 (2003). https://doi.org/10.1038/nature02009

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature02009

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing