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Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours

Abstract

Activation of the Hedgehog (Hh) signalling pathway by sporadic mutations or in familial conditions such as Gorlin's syndrome is associated with tumorigenesis in skin, the cerebellum and skeletal muscle1,2. Here we show that a wide range of digestive tract tumours, including most of those originating in the oesophagus, stomach, biliary tract and pancreas, but not in the colon, display increased Hh pathway activity, which is suppressible by cyclopamine, a Hh pathway antagonist. Cyclopamine also suppresses cell growth in vitro and causes durable regression of xenograft tumours in vivo. Unlike in Gorlin's syndrome tumours, pathway activity and cell growth in these digestive tract tumours are driven by endogenous expression of Hh ligands, as indicated by the presence of Sonic hedgehog and Indian hedgehog transcripts, by the pathway- and growth-inhibitory activity of a Hh-neutralizing antibody, and by the dramatic growth-stimulatory activity of exogenously added Hh ligand. Our results identify a group of common lethal malignancies in which Hh pathway activity, essential for tumour growth, is activated not by mutation but by ligand expression.

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Figure 1: Hh pathway activity in normal and neoplastic gut cells and tissues.
Figure 2: Cyclopamine suppression of Hh pathway activity and growth in digestive tract tumour cell lines correlates with expression of PTCH mRNA.
Figure 3: Hh pathway activity and requirement for growth of tumour cells in vivo.
Figure 4: Ligand dependence of Hh pathway activity and growth in digestive tract tumours.

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Acknowledgements

We thank E. Traband and K. Young for technical assistance, E. Montgomery, K. Miyazaki and J. Harmon for cell lines, J. Chen for help with cyclopamine purification and P. Fussell for help with figures. This work was supported by the family of Margaret Lee and grants from the National Institutes of Health (D.M.B., A.M., J.R.E. and P.A.B.). P.A.B. is an investigator and M.R.G. a medical fellow of the Howard Hughes Medical Institute.

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Correspondence to Philip A. Beachy.

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Under a licensing agreement between Curis, Inc. and the Johns Hopkins University, P. A. Beachy and the University hold equity in Curis and are entitled to a share of royalties from sales of the products described in this article. P. A. Beachy also receives payment and equity for service as a consultant to Curis, Inc. The terms of this arrangement are being managed by the Johns Hopkins University in accordance with its conflict of interest policies.

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Berman, D., Karhadkar, S., Maitra, A. et al. Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours. Nature 425, 846–851 (2003). https://doi.org/10.1038/nature01972

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