A paracrine requirement for hedgehog signalling in cancer (original) (raw)

Nature volume 455, pages 406–410 (2008)Cite this article

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.

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Primary accessions

Gene Expression Omnibus

Data deposits

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

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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.

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Author notes

  1. Karen Kotkow & Lee L. Rubin
    Present address: Present address: Harvard Stem Cell Institute, Harvard University, Biolabs Room 1065, 16 Divinity Avenue, Cambridge, Massachusetts 02138, USA.,
  2. Robert L. Yauch and Stephen E. Gould: These authors contributed equally to this work.

Authors and Affiliations

  1. Genentech Inc., 1 DNA Way, South San Francisco, California 94080, USA ,
    Robert L. Yauch, Stephen E. Gould, Suzie J. Scales, Tracy Tang, Hua Tian, Christina P. Ahn, Derek Marshall, Ling Fu, Thomas Januario, Dara Kallop, Michelle Nannini-Pepe, James C. Marsters & Frederic J. de Sauvage
  2. Curis Inc., 45 Moulton Street, Cambridge, Massachusetts 02138, USA ,
    Karen Kotkow & Lee L. Rubin

Authors

  1. Robert L. Yauch
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  2. Stephen E. Gould
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  3. Suzie J. Scales
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  4. Tracy Tang
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  5. Hua Tian
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  6. Christina P. Ahn
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  7. Derek Marshall
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  8. Ling Fu
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  9. Thomas Januario
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  10. Dara Kallop
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  11. Michelle Nannini-Pepe
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  12. Karen Kotkow
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  13. James C. Marsters
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  14. Lee L. Rubin
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  15. Frederic J. de Sauvage
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Corresponding author

Correspondence toFrederic J. de Sauvage.

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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.

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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

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Editorial Summary

Hedgehog signalling in cancer

The hedgehog (Hh) signalling pathway acts in the developing embryo as part of the network controlling cell proliferation and cell fate. It has also been implicated in a number of solid tumours, where it was thought to mediate tumour cell proliferation directly. But a new study suggests a rather different role for hedgehog in cancers. Hedgehog ligands secreted by cancer cells failed to activate signalling in tumour epithelial cells but instead acted on the stroma, the mass of extracellular matrix, fibroblasts, endothelial cells and microvasculature in which the malignant cells are embedded. Tumour growth was promoted, but apparently via an effect on the tumour cells' microenvironment. These findings have important implications for the use of hedgehog antagonists as anticancer drugs.

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