Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours.
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.
Berman
David M
DM
Department of Molecular Biology and Genetics and Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Karhadkar
Sunil S
SS
Maitra
Anirban
A
Montes De Oca
Rocio
R
Gerstenblith
Meg R
MR
Briggs
Kimberly
K
Parker
Antony R
AR
Shimada
Yutaka
Y
Eshleman
James R
JR
Watkins
D Neil
DN
Beachy
Philip A
PA
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D004064:Digestive System / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D053823:Hedgehog Proteins; D006801:Humans; D008024:Ligands; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D009368:Neoplasm Transplantation; D000072079:Patched Receptors; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface; D015398:Signal Transduction / Q000187:drug effects; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D014183:Transplantation, Heterologous; D014704:Veratrum Alkaloids / Q000494:pharmacology / Q000627:therapeutic use
D053823:Hedgehog Proteins; D008024:Ligands; D008565:Membrane Proteins; D000072079:Patched Receptors; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D011956:Receptors, Cell Surface; C509239:SHH protein, human; D015534:Trans-Activators; D014704:Veratrum Alkaloids; C000541:cyclopamine