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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Methylation of PTCH1a gene in a subset of gastric cancers.
Peng Du,Hai-Rong Ye,Jun Gao,Wei Chen,Zhongchuan Wang,Honghua Jiang,Ji Xu,Ji-We Zhang,Jian-Cheng Zhang,Long Cui +9 more
TL;DR: Methylation of PTCH1a TRR is present in a subset of gastric cancers and correlated negatively withPTCH1 expression, which may be an early event in gastric tumorigenesis and a new treatment target.
Journal ArticleDOI
Discovery of novel hedgehog antagonists from cell-based screening: Isosteric modification of p38 bisamides as potent inhibitors of SMO.
Bin Yang,Alexander Hird,Daniel John Russell,Benjamin Fauber,Les A. Dakin,Xiaolan Zheng,Qibin Su,Robert Godin,Patrick Brassil,Erik Devereaux,James W. Janetka +10 more
TL;DR: The identification of advanced lead compounds such as imidazole 11c and 11f encompassing good p38α selectivity, low nanomolar potency in both cell assays, excellent physiochemical properties and in vivo pharmacokinetics is reported.
Journal ArticleDOI
A perspective on molecular therapy in cholangiocarcinoma: present status and future directions.
TL;DR: Current clinical attempts for targeted therapy of CCA are emphasized, as well as promising new candidate pathways revealed by translational genomics are highlighted.
Journal ArticleDOI
Forskolin, a Hedgehog signal inhibitor, inhibits cell proliferation and induces apoptosis in pediatric tumor cell lines
TL;DR: It is demonstrated that Hh signal activation frequently occurs in neuroblastoma, hepatoblastoma and rhabdomyosarcoma cell lines, and is a potential molecular target of new treatment strategies for these pediatric malignant tumors.
Journal ArticleDOI
Expression of glioma-associated oncogene homolog 1 is associated with invasion and postoperative liver metastasis in colon cancer.
TL;DR: In patients with colon cancer, Gli-1 expression level is closely related to lymph node metastases, T stages and postoperative live metastasis-free survival periods, indicative of a possible role of Gli -1 expression in colon cancer progression.
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
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