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
Hedgehog Signal Activation in Gastric Pit Cell and in Diffuse-Type Gastric Cancer
Masahide Fukaya,Noriyuki Isohata,Hiroyuki Ohta,Kazuhiko Aoyagi,Takahiro Ochiya,Norihisa Saeki,Kazuyoshi Yanagihara,Yukihiro Nakanishi,Hirokazu Taniguchi,Hiromi Sakamoto,Tadakazu Shimoda,Yuji Nimura,Teruhiko Yoshida,Hiroki Sasaki +13 more
TL;DR: expression of IHH and downstream targets correlates with pit cells, and I HH and SMO may be useful biomarkers of diffuse cancers that may show growth inhibition with Hh antagonists such as cyclopamine.
Journal ArticleDOI
Hedgehog pathway antagonist 5E1 binds hedgehog at the pseudo-active site.
Henry R. Maun,Xiaohui Wen,Andreas Lingel,Frederic J. de Sauvage,Robert A. Lazarus,Suzie J. Scales,Sarah G. Hymowitz +6 more
TL;DR: The ch5E1 Fab-Shh complex represents the first structure of an inhibitor antibody bound to a metalloprotease fold and shows that, like the regulatory receptors Cdon and Hedgehog-interacting protein (Hhip), ch4E1 binding to Sonic hedgehog (Shh) is enhanced by calcium ions.
Journal ArticleDOI
Context-dependent signal integration by the GLI code: the oncogenic load, pathways, modifiers and implications for cancer therapy.
TL;DR: The concepts of the GLI code, the oncogenic load, the context-dependency of GLI action, and different modes of signaling integration such as that of HH and EGF are highlighted.
Journal ArticleDOI
Clear Cell Sarcoma of the Kidney: Up-regulation of Neural Markers with Activation of the Sonic Hedgehog and Akt Pathways
Colleen Cutcliffe,Donna Kersey,Chiang Ching Huang,Yong Zeng,David O. Walterhouse,Elizabeth J. Perlman +5 more
TL;DR: This study suggests that CCSKs arise within a renal mesenchymal cell that shows a wide variety of neural markers, and seems to be susceptible to genetic changes also seen in a variety of other neuroectodermal and neuronal tumors, including activation of Sonic hedgehog and phosphoinositide-3-kinase/Akt pathways.
Journal ArticleDOI
Hedgehog signaling overrides p53-mediated tumor suppression by activating Mdm2.
Yoshinori Abe,Eri Oda-Sato,Kei Tobiume,Keiko Kawauchi,Yoichi Taya,Koji Okamoto,Moshe Oren,Nobuyuki Tanaka +7 more
TL;DR: It is found that accumulation of p53 is inhibited by Hh signaling in several human cancer cell lines, suggesting that the Hh pathway may be a powerful accelerator of oncogenesis by activating cell proliferation and inhibiting the p53-mediated anti-cancer barrier induced by oncogenic stress.
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
TL;DR: Osteoblastic cells are a regulatory component of the haematopoietic stem cell niche in vivo that influences stem cell function through Notch activation.
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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
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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