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

David M. Berman, Sunil S. Karhadkar, Anirban Maitra, Rocio Montes de Oca, Meg R. Gerstenblith, Kimberly Briggs, Antony R. Parker, Yutaka Shimada, James R. Eshleman, D. Neil Watkins and Philip A. Beachy ()
Additional contact information
David M. Berman: Johns Hopkins University School of Medicine
Sunil S. Karhadkar: Johns Hopkins University School of Medicine
Anirban Maitra: Johns Hopkins University School of Medicine
Rocio Montes de Oca: Johns Hopkins University School of Medicine
Meg R. Gerstenblith: Johns Hopkins University School of Medicine
Kimberly Briggs: Johns Hopkins University School of Medicine
Antony R. Parker: Johns Hopkins University School of Medicine
Yutaka Shimada: Kyoto University
James R. Eshleman: Johns Hopkins University School of Medicine
D. Neil Watkins: Johns Hopkins University School of Medicine
Philip A. Beachy: Johns Hopkins University School of Medicine

Nature, 2003, vol. 425, issue 6960, 846-851

Abstract: 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.

Date: 2003
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DOI: 10.1038/nature01972

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