Journal ArticleDOI
Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours
David M. Berman,Sunil S. Karhadkar,Anirban Maitra,Rocío Montes de Oca,Meg R. Gerstenblith,Kimberly J. Briggs,Antony R. Parker,Yutaka Shimada,James R. Eshleman,D. Neil Watkins,Philip A. Beachy +10 more
TLDR
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 pathways antagonist.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.read more
Citations
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Patent
Pyridazine derivatives as smo inhibitors
TL;DR: In this article, the authors describe novel compounds relating to the diagnosis and treatment of pathologies related to the Hedgehog pathway, including but not limited to tumor formation, cancer, neoplasia, and non-malignant hyperproliferative disorders.
Journal ArticleDOI
Pancreatic Cancer and Hedgehog Pathway Signaling: New Insights
TL;DR: Together, these findings present new insights into how modulation of this pathway may allow us to target multiple aspects of pancreatic tumor biology.
Journal ArticleDOI
Inhibition of endogenous hedgehog signaling protects against acute liver injury after ischemia reperfusion.
TL;DR: Evidence is provided that endogenous Hh signaling is an early mediator of liver injury and inflammation after I/R and this novel strategy of preconditioning livers with Hh antagonist may have effective therapeutic potential in preventing acute liver injury.
Journal ArticleDOI
Identification of a novel Smoothened antagonist that potently suppresses Hedgehog signaling.
Jiangbo Wang,Robert A. Mook,Jiuyi Lu,David M. Gooden,Anthony A. Ribeiro,Anchen Guo,Larry S. Barak,H. Kim Lyerly,Wei Chen +8 more
TL;DR: The use of this assay in the antagonist mode is reported to identify novel antagonists of Smoothened, including a compound (A8) with low nanomolar activity against wild-type Smo also capable of binding the Smo point mutant D473H associated with clinical resistance in medulloblastoma.
Journal ArticleDOI
In vitro models of pancreatic cancer for translational oncology research
TL;DR: Although in vitro models of pancreatic cancer are of tremendous value for genetic studies and for initial functional screenings in drug discovery, they carry several immanent drawbacks and are often poor in predicting therapeutic response in humans.
References
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Osteoblastic cells regulate the haematopoietic stem cell niche
Laura M. Calvi,Gregor B. Adams,Kathryn W. Weibrecht,Jonathan M. Weber,David P. Olson,M. C. Knight,Roderick P. Martin,Ernestina Schipani,P. Divieti,F. R. Bringhurst,Laurie A. Milner,Henry M. Kronenberg,David T. Scadden +12 more
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Jiwang Zhang,Chao Niu,Ling Ye,Haiyang Huang,Xi C. He,Wei Gang Tong,Jason Ross,Jeffrey S. Haug,Teri Johnson,Jian Q. Feng,Stephen E. Harris,Leanne M. Wiedemann,Leanne M. Wiedemann,Yuji Mishina,Linheng Li,Linheng Li +15 more
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Hedgehog signaling in animal development: paradigms and principles.
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Journal ArticleDOI
Purification and Characterization of Mouse Hematopoietic Stem Cells
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Journal ArticleDOI
A clonogenic common myeloid progenitor that gives rise to all myeloid lineages
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