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.

A paracrine requirement for hedgehog signalling in cancer

Abstract

Ligand-dependent activation of the hedgehog (Hh) signalling pathway has been associated with tumorigenesis in a number of human tissues1,2,3,4,5,6,7. Here we show that, although previous reports have described a cell-autonomous role for Hh signalling in these tumours1,2,3,4,5,6,7, Hh ligands fail to activate signalling in tumour epithelial cells. In contrast, our data support ligand-dependent activation of the Hh pathway in the stromal microenvironment. Specific inhibition of Hh signalling using small molecule inhibitors, a neutralizing anti-Hh antibody or genetic deletion of smoothened (Smo) in the mouse stroma results in growth inhibition in xenograft tumour models. Taken together, these studies demonstrate a paracrine requirement for Hh ligand signalling in the tumorigenesis of Hh-expressing cancers and have important implications for the development of Hh pathway antagonists in cancer.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Lack of Hh pathway activation in human cancer cell lines.
Figure 2: Human Hh ligands are overexpressed in a subset of human cancers and can activate Hh signalling in a paracrine manner.
Figure 3: Inhibition of the Hh pathway results in a significant delay in the growth of Hh ligand-expressing tumours in vivo.
Figure 4: Stromal hedgehog signalling can support tumour growth.

Accession codes

Primary accessions

Gene Expression Omnibus

Data deposits

Microarray data are deposited in the NCBI GEO database under accession number GSE11981.

References

  1. 1

    Clement, V., Sanchez, P., de Tribolet, N., Radovanovic, I. & Ruiz i Altaba, A. HEDGEHOG–GLI1 signaling regulates human glioma growth, cancer stem cell self-renewal, and tumorigenicity. Curr. Biol. 17, 165–172 (2007)

    CAS  Article  Google Scholar 

  2. 2

    Stecca, B. et al. Melanomas require HEDGEHOG–GLI signaling regulated by interactions between GLI1 and the RAS-MEK/AKT pathways. Proc. Natl Acad. Sci. USA 104, 5895–5900 (2007)

    ADS  CAS  Article  Google Scholar 

  3. 3

    Yuan, Z. et al. Frequent requirement of hedgehog signaling in non-small cell lung carcinoma. Oncogene 26, 1046–1055 (2007)

    CAS  Article  Google Scholar 

  4. 4

    Thayer, S. P. et al. Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature 425, 851–856 (2003)

    ADS  CAS  Article  Google Scholar 

  5. 5

    Karhadkar, S. S. et al. Hedgehog signalling in prostate regeneration, neoplasia and metastasis. Nature 431, 707–712 (2004)

    ADS  CAS  Article  Google Scholar 

  6. 6

    Berman, D. M. et al. Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours. Nature 425, 846–851 (2003)

    ADS  CAS  Article  Google Scholar 

  7. 7

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

    ADS  CAS  Article  Google Scholar 

  8. 8

    Ingham, P. W. & McMahon, A. P. Hedgehog signaling in animal development: paradigms and principles. Genes Dev. 15, 3059–3087 (2001)

    CAS  Article  Google Scholar 

  9. 9

    van den Brink, G. R. Hedgehog signaling in development and homeostasis of the gastrointestinal tract. Physiol. Rev. 87, 1343–1375 (2007)

    CAS  Article  Google Scholar 

  10. 10

    Romer, J. T. et al. Suppression of the Shh pathway using a small molecule inhibitor eliminates medulloblastoma in Ptc1+/-p53-/- mice. Cancer Cell 6, 229–240 (2004)

    CAS  Article  Google Scholar 

  11. 11

    Frank-Kamenetsky, M. et al. Small-molecule modulators of Hedgehog signaling: identification and characterization of Smoothened agonists and antagonists. J. Biol. 1, 10 (2002)

    Article  Google Scholar 

  12. 12

    Cooper, M. K., Porter, J. A., Young, K. E. & Beachy, P. A. Teratogen-mediated inhibition of target tissue response to Shh signaling. Science 280, 1603–1607 (1998)

    ADS  CAS  Article  Google Scholar 

  13. 13

    Kayed, H. et al. Indian hedgehog signaling pathway: expression and regulation in pancreatic cancer. Int. J. Cancer 110, 668–676 (2004)

    CAS  Article  Google Scholar 

  14. 14

    Fan, C. M. et al. Long-range sclerotome induction by sonic hedgehog: direct role of the amino-terminal cleavage product and modulation by the cyclic AMP signaling pathway. Cell 81, 457–465 (1995)

    CAS  Article  Google Scholar 

  15. 15

    Sasai, K. et al. Shh pathway activity is down-regulated in cultured medulloblastoma cells: implications for preclinical studies. Cancer Res. 66, 4215–4222 (2006)

    CAS  Article  Google Scholar 

  16. 16

    Duda, D. G. et al. Differential transplantability of tumor-associated stromal cells. Cancer Res. 64, 5920–5924 (2004)

    CAS  Article  Google Scholar 

  17. 17

    Hayashi, S. & McMahon, A. P. Efficient recombination in diverse tissues by a tamoxifen-inducible form of Cre: a tool for temporally regulated gene activation/inactivation in the mouse. Dev. Biol. 244, 305–318 (2002)

    CAS  Article  Google Scholar 

  18. 18

    Long, F., Zhang, X. M., Karp, S., Yang, Y. & McMahon, A. P. Genetic manipulation of hedgehog signaling in the endochondral skeleton reveals a direct role in the regulation of chondrocyte proliferation. Development 128, 5099–5108 (2001)

    CAS  PubMed  Google Scholar 

  19. 19

    Beachy, P. A., Karhadkar, S. S. & Berman, D. M. Tissue repair and stem cell renewal in carcinogenesis. Nature 432, 324–331 (2004)

    ADS  CAS  Article  Google Scholar 

  20. 20

    Fan, L. et al. Hedgehog signaling promotes prostate xenograft tumor growth. Endocrinology 145, 3961–3970 (2004)

    CAS  Article  Google Scholar 

  21. 21

    Pola, R. et al. The morphogen Sonic hedgehog is an indirect angiogenic agent upregulating two families of angiogenic growth factors. Nature Med. 7, 706–711 (2001)

    CAS  Article  Google Scholar 

  22. 22

    Ingram, W. J., Wicking, C. A., Grimmond, S. M., Forrest, A. R. & Wainwright, B. J. Novel genes regulated by Sonic Hedgehog in pluripotent mesenchymal cells. Oncogene 21, 8196–8205 (2002)

    CAS  Article  Google Scholar 

  23. 23

    Bergmann, U., Funatomi, H., Yokoyama, M., Beger, H. G. & Korc, M. Insulin-like growth factor I overexpression in human pancreatic cancer: evidence for autocrine and paracrine roles. Cancer Res. 55, 2007–2011 (1995)

    CAS  PubMed  Google Scholar 

  24. 24

    Durai, R., Yang, W., Gupta, S., Seifalian, A. M. & Winslet, M. C. The role of the insulin-like growth factor system in colorectal cancer: review of current knowledge. Int. J. Colorectal Dis. 20, 203–220 (2005)

    Article  Google Scholar 

  25. 25

    Zeng, G. et al. Aberrant Wnt/β-catenin signaling in pancreatic adenocarcinoma. Neoplasia 8, 279–289 (2006)

    CAS  Article  Google Scholar 

  26. 26

    Pasca di Magliano, M. et al. Common activation of canonical wnt signaling in pancreatic adenocarcinoma. PLoS ONE 2, e1155 (2007)

    ADS  Article  Google Scholar 

  27. 27

    Bhowmick, N. A., Neilson, E. G. & Moses, H. L. Stromal fibroblasts in cancer initiation and progression. Nature 432, 332–337 (2004)

    ADS  CAS  Article  Google Scholar 

  28. 28

    Orimo, A. & Weinberg, R. A. Stromal fibroblasts in cancer: a novel tumor-promoting cell type. Cell Cycle 5, 1597–1601 (2006)

    CAS  Article  Google Scholar 

  29. 29

    Ericson, J., Morton, S., Kawakami, A., Roelink, H. & Jessell, T. M. Two critical periods of Sonic Hedgehog signaling required for the specification of motor neuron identity. Cell 87, 661–673 (1996)

    CAS  Article  Google Scholar 

  30. 30

    Yoneda, T. & Pratt, R. M. Mesenchymal cells from the human embryonic palate are highly responsive to epidermal growth factor. Science 213, 563–565 (1981)

    ADS  CAS  Article  Google Scholar 

Download references

Acknowledgements

The authors thank A. McMahon and M. Scott for providing transgenic mice; T. Holcomb, K. Wagner, D. Lee and P. Wen for their assistance in cell line screening; J. Ernst for rSHH, M. Cole for assistance with imaging; S. Louie for assistance with graphics; P. Haverty for assistance with gene expression data; and M. Evangelista, C. Callahan and V. Dixit for comments and discussions. Tissue samples were provided by the Cooperative Human Tissue Network, which is funded by the National Cancer Institute, and the National Center for Research Resources, which is supported by the National Institutes of Health. Other investigators may have received samples from these same tissues.

Author Contributions F.J.d.S. and L.L.R. conceived and directed the project. S.E.G., R.L.Y., S.J.S., T.T., H.T. J.C.M. and K.K. designed and carried out experiments. C.P.A., D.M., L.F., T.J., D.K. and M.N.-P. carried out experiments. R.L.Y., S.E.G. and F.J.d.S. wrote the paper.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Frederic J. de Sauvage.

Ethics declarations

Competing interests

R.L.Y., S.E.G., S.J.S., T.T., H.T., C.A., D.M., L.F., T.J., D.K., M.N.-P., J.C.M. and F.J.d.S. are employed by Genentech, Inc. and/or may have stocks or shares in Genentech, Inc.

Supplementary information

Supplementary Information 1

This file contains Supplementary Methods, Supplementary Tables 1-3 and Supplementary Figures 1-13. (PDF 3308 kb)

Supplementary Information 2

This file contains supplemental microarray data. (XLS 16739 kb)

Supplementary Information 3

This file contains supplemental microarray data. (XLS 14492 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Yauch, R., Gould, S., Scales, S. et al. A paracrine requirement for hedgehog signalling in cancer. Nature 455, 406–410 (2008). https://doi.org/10.1038/nature07275

Download citation

Further reading

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

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