TY - JOUR
T1 - Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours
AU - Berman, David M.
AU - Karhadkar, Sunil S.
AU - Maitra, Anirban
AU - De Oca, Rocio Montes
AU - Gerstenblith, Meg R.
AU - Briggs, Kimberly
AU - Parker, Antony R.
AU - Shimada, Yutaka
AU - Eshleman, James R.
AU - Watkins, D. Neil
AU - Beachy, Philip A.
N1 - Funding Information:
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.
Funding Information:
Acknowledgements The authors thank J. Harvey for assistance with histological analyses. This work was supported by the National Institutes of Health (L.M.C., H.M.K., E.S. and D.T.S.), the American Society of Hematology Fellow Scholar Award (G.B.A.) and the Doris Duke Foundational Burroughs Wellcome Fund (D.T.S.) Competing interests statement The authors declare competing financial interests: details accompany the paper on www.nature.com/nature.
PY - 2003/10/23
Y1 - 2003/10/23
N2 - 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.
AB - 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.
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U2 - 10.1038/nature01972
DO - 10.1038/nature01972
M3 - Article
C2 - 14520411
AN - SCOPUS:0242268525
SN - 0028-0836
VL - 425
SP - 846
EP - 851
JO - Nature
JF - Nature
IS - 6960
ER -