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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Journal ArticleDOI
Pancreatic Cancer: Basic and Clinical Aspects
Journal ArticleDOI
Small-molecule inhibitors reveal multiple strategies for Hedgehog pathway blockade
Joel M. Hyman,Ari J. Firestone,Vivi M. Heine,Yun Zhao,Cory A. Ocasio,Kyuho Han,Mark Sun,Paul G. Rack,Surajit Sinha,Surajit Sinha,Jason Wu,David E. Solow-Cordero,Jin Jiang,David H. Rowitch,James K. Chen +14 more
TL;DR: Four Hh pathway antagonists that are epistatic to the nucleocytoplasmic regulator Suppressor of Fused are reported, including two that can inhibit Hh target gene expression induced by overexpression of the Gli transcription factors and reveal that Gli processing, Gli activation, and primary cilia formation are pharmacologically targetable.
Journal ArticleDOI
Hedgehog/Ras interactions regulate early stages of pancreatic cancer.
Marina Pasca di Magliano,Shigeki Sekine,Alexandre N. Ermilov,Jenny Ferris,Andrzej A. Dlugosz,Matthias Hebrok +5 more
TL;DR: A mouse model in which Hedgehog signaling is activated specifically in the pancreatic epithelium indicates the cooperation of Hedgehog and Ras signaling during the earliest stages of PDA formation and marks Hedgehog pathway components as relevant therapeutic targets for both early and advanced stages of pancreatic ductal neoplasia.
Journal ArticleDOI
Context-Dependent Transformation of Adult Pancreatic Cells by Oncogenic K-Ras
Sharon Y. Gidekel Friedlander,Gerald C. Chu,Eric L. Snyder,Nomeda Girnius,Gregory Dibelius,Denise Crowley,Eliza Vasile,Ronald A. DePinho,Tyler Jacks +8 more
TL;DR: In this paper, the effect of PDAC-relevant gene mutations in distinct cell types of the adult pancreas was investigated and it was shown that a subpopulation of Pdx1-expressing cells is susceptible to oncogenic K-Ras-induced transformation without tissue injury.
Journal ArticleDOI
Activity-Dependent Internalization of Smoothened Mediated by ß-Arrestin 2 and GRK2
Wei Chen,Xiu-Rong Ren,Christopher D. Nelson,Larry S. Barak,James K. Chen,Philip A. Beachy,Frederic J. de Sauvage,Robert J. Lefkowitz +7 more
TL;DR: It is found that two molecules interact with mammalian Smo in an activation-dependent manner: G protein–coupled receptor kinase 2 (GRK2) leads to phosphorylation of Smo, and β-arrestin 2 fused to green fluorescent protein interacts with Smo.
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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Identification of the haematopoietic stem cell niche and control of the niche size
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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Journal ArticleDOI
Hedgehog signaling in animal development: paradigms and principles.
TL;DR: In their screen for mutations that disrupt the Drosophila larval body plan, these authors identified several that cause the duplication of denticles and an accompanying loss of naked cuticle, characteristic of the posterior half of each segment.
Journal ArticleDOI
Purification and Characterization of Mouse Hematopoietic Stem Cells
TL;DR: Mouse bone marrow hematopoietic stem cells were isolated with the use of a variety of phenotypic markers and thirty of these cells are sufficient to save 50 percent of lethally irradiated mice, and to reconstitute all blood cell types in the survivors.
Journal ArticleDOI
A clonogenic common myeloid progenitor that gives rise to all myeloid lineages
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