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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Protein Phosphatase 2A and Rapamycin Regulate the Nuclear Localization and Activity of the Transcription Factor GLI3
TL;DR: The findings reveal the existence of a hitherto unrecognized molecular cross-talk between the oncogenic SHH pathway and the tumor suppressor PP2A and suggest a novel mechanism underlying the anticancerogenic effects of rapamycin.
Journal Article
Correction to Evidence for Allosteric Interactions of Antagonist Binding to the Smoothened Receptor
Cynthia M. Rominger,Weilin Tiger Bee,Robert A. Copeland,Elizabeth A. Davenport,Aidan G. Gilmartin,Richard R. Gontarek,Keith R. Hornberger,Lorena A. Kallal,Zhihong Lai,Kenneth W. M. Lawrie,Quinn Lu,Mcmillan Lynette Jane,Maggie Truong,Peter J. Tummino,Brandon J. Turunen,M. Will,William J. Zuercher,David H. Rominger +17 more
TL;DR: In this article, the biochemical characterization of allosteric interactions of small-molecule antagonists of Smo with the hedgehog pathway has been reported, and two structurally distinct Smoothened receptor antagonists (SANT-1 and SANT-2) have been found to fully inhibit the Hh pathway activation.
Journal ArticleDOI
Cyclopamine increases the cytotoxic effects of paclitaxel and radiation but not cisplatin and gemcitabine in Hedgehog expressing pancreatic cancer cells
TL;DR: Strategies to combine Hh inhibitors with radiotherapy and chemotherapeutic agents, specifically paclitaxel and related compounds in the treatment of pancreatic cancer are suggested.
Journal ArticleDOI
Aberrant signaling pathways in pancreatic cancer: A two compartment view
TL;DR: The formation of complex signaling networks of communication between the tumor epithelial cell and the stromal cell compartments to promote a permissive and cooperative environment is highlighted.
Journal ArticleDOI
Reduced Level of Smoothened Suppresses Intestinal Tumorigenesis by Down-Regulation of Wnt Signaling
Sumimasa Arimura,Akihiro Matsunaga,Takanori Kitamura,Koji Aoki,Masahiro Aoki,Makoto Mark Taketo +5 more
TL;DR: Smo contributes to intestinal tumorigenesis by increasing Wnt signaling by reducing protein levels of active beta-catenin and induced its nuclear exclusion, and might be a good therapeutic target for patients with colorectal polyps and carcinomas, even in the absence of Hh signal activation.
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
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
TL;DR: The prospective identification, purification and characterization, using cell-surface markers and flow cytometry, of a complementary clonogenic common myeloid progenitor that gives rise to all myeloids lineages is reported.
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