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A paracrine requirement for hedgehog signalling in cancer


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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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.

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Gene Expression Omnibus

Data deposits

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


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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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Correspondence to Frederic J. de Sauvage.

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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)

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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).

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