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
Genetic variations in the sonic hedgehog pathway affect clinical outcomes in non-muscle-invasive bladder cancer.
Meng Chen,Michelle A.T. Hildebrandt,Jessica Clague,Ashish M. Kamat,Antoni Picornell,Joshua Chang,Xiaofan Zhang,Julie G. Izzo,Hushan Yang,Jie Lin,Jian Gu,Stephen J. Chanock,Manolis Kogevinas,Nathaniel Rothman,Debra T. Silverman,Montserrat Garcia-Closas,H. Barton Grossman,Colin P.N. Dinney,Núria Malats,Xifeng Wu +19 more
TL;DR: Although three SNPs showed nominal significance in association with overall survival in MiMBC patients, none remained significant after multiple-comparison adjustments, and the wild-type genotype of either of these SNPs was associated with a lower recurrence rate and longer recurrence-free survival.
Journal ArticleDOI
PTCH1, a receptor of Hedgehog signaling pathway, is correlated with metastatic potential of colorectal cancer
TL;DR: The data suggest that PTCH1 might be a potential biomarker that could discriminate CRC with high from that with low metastatic risk, and inversely correlated with the metastatic potential of CRC cell lines.
Journal ArticleDOI
Discovery and preclinical development of vismodegib.
Stephen E. Gould,Jennifer A. Low,James C. Marsters,Kirk Robarge,Lee L. Rubin,Frederic J. de Sauvage,Daniel P. Sutherlin,Harvey Wong,Robert L. Yauch +8 more
TL;DR: This article reviews the development of vismodegib from its discovery, preclinical pharmacology and validation to the clinical pharmacokinetics and validation in Phase I and II clinical investigations and provides a survey of other Hh pathway inhibitors in clinical development.
Journal ArticleDOI
Stroma and pancreatic ductal adenocarcinoma: an interaction loop.
TL;DR: It is proposed that the extensive stroma of PDA is closely linked to its poor prognosis, and targeting the stroma may provide novel prevention, earlier detection and therapeutic options to this deadly malignancy.
Journal ArticleDOI
Mechanisms of Hedgehog signalling in cancer
TL;DR: There is now increasing evidence suggesting that ‘non-canonical’ Hh signalling mechanisms, some of which are independent of GLI-mediated transcription, may be important in cancer and development.
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
TL;DR: It is concluded that SNO cells lining the bone surface function as a key component of the niche to support HSCs, and that BMP signalling through BMPRIA controls the number of H SCs by regulating niche size.
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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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