1. Genentech Inc., 1 DNA Way, South San Francisco, California 94080, USA
2. Curis Inc., 45 Moulton Street, Cambridge, Massachusetts 02138, USA
3. These authors contributed equally to this work.
4. Present address: Harvard Stem Cell Institute, Harvard University, Biolabs Room 1065, 16 Divinity Avenue, Cambridge, Massachusetts 02138, USA.

Correspondence to: Frederic J. de Sauvage¹ Correspondence and requests for materials should be addressed to F.J.d.S. (Email: sauvage@gene.com).

Abstract

Ligand-dependent activation of the hedgehog (Hh) signalling pathway has been associated with tumorigenesis in a number of human tissues^{1, 2, 3, 4, 5, 6, 7}. Here we show that, although previous reports have described a cell-autonomous role for Hh signalling in these tumours^{1, 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.

1. Genentech Inc., 1 DNA Way, South San Francisco, California 94080, USA
2. Curis Inc., 45 Moulton Street, Cambridge, Massachusetts 02138, USA
3. These authors contributed equally to this work.
4. Present address: Harvard Stem Cell Institute, Harvard University, Biolabs Room 1065, 16 Divinity Avenue, Cambridge, Massachusetts 02138, USA.

Correspondence to: Frederic J. de Sauvage¹ Correspondence and requests for materials should be addressed to F.J.d.S. (Email: sauvage@gene.com).

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