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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Cell Division / drug effects
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Cell Line, Tumor
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Digestive System / cytology
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Digestive System / drug effects
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Digestive System / metabolism
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Digestive System / pathology
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Gastrointestinal Neoplasms / drug therapy
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Gastrointestinal Neoplasms / genetics
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Gastrointestinal Neoplasms / metabolism*
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Gastrointestinal Neoplasms / pathology*
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Gene Deletion
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Gene Expression Regulation, Neoplastic*
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Hedgehog Proteins
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Humans
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Ligands
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Mice
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Mice, Nude
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Mutation
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Neoplasm Transplantation
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Patched Receptors
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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RNA, Neoplasm / genetics
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RNA, Neoplasm / metabolism
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Receptors, Cell Surface
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Signal Transduction* / drug effects
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Trans-Activators / antagonists & inhibitors
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Trans-Activators / genetics*
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Trans-Activators / metabolism*
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Transplantation, Heterologous
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Veratrum Alkaloids / pharmacology
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Veratrum Alkaloids / therapeutic use
Substances
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Hedgehog Proteins
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Ligands
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Membrane Proteins
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Patched Receptors
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RNA, Messenger
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RNA, Neoplasm
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Receptors, Cell Surface
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SHH protein, human
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Trans-Activators
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Veratrum Alkaloids
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cyclopamine