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, Philip A. Beachy

Research output: Contribution to journalArticlepeer-review

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 muscle. 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.

Original languageEnglish (US)
Pages (from-to)846-851
Number of pages6
JournalNature
Volume425
Issue number6960
DOIs
StatePublished - Oct 23 2003

ASJC Scopus subject areas

  • General

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