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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Transient inhibition of the Hedgehog pathway in young mice causes permanent defects in bone structure.
TL;DR: Although pathway activity was restored 2 days after drug removal, brief inhibition caused permanent defects in bone growth, and HhAntag inhibited proliferation and promoted differentiation of chondrocytes, leading to dramatic expansion of the hypertrophic zone.
Journal ArticleDOI
Snail induction is an early response to Gli1 that determines the efficiency of epithelial transformation.
Xingnan Li,W Deng,Clinton D. Nail,Sarah K. Bailey,Matthias H. Kraus,J M Ruppert,Susan M. Lobo-Ruppert +6 more
TL;DR: The results identify Snail as a Gli1-inducible effector of transformation in vitro, and an early Gli 1-responsive gene in the skin.
Journal ArticleDOI
Hedgehog signalling in colorectal tumour cells: Induction of apoptosis with cyclopamine treatment
TL;DR: It is suggested that autocrine Hh signalling can increase aberrant cell survival in colorectal tumour cells and may be a novel target for colon cancer therapy using drugs such as cyclopamine.
Journal ArticleDOI
Nuclear Factor-κB Contributes to Hedgehog Signaling Pathway Activation through Sonic Hedgehog Induction in Pancreatic Cancer
Hiroshi Nakashima,Masafumi Nakamura,Hiroshi Yamaguchi,Naoki Yamanaka,T. Akiyoshi,Kenichiro Koga,Koji Yamaguchi,Masazumi Tsuneyoshi,Masao Tanaka,Mitsuo Katano +9 more
TL;DR: The present study found a close positive correlation between NF-kappaB p65 and Shh expression in surgically resected pancreas specimens, including specimens of chronic pancreatitis and pancreatic adenocarcinoma, and showed that blockade of NF- kappaB suppressed constitutive expression of Shh mRNA in pancreatic cancer cells.
Journal ArticleDOI
miR‐25 targets TNF‐related apoptosis inducing ligand (TRAIL) death receptor‐4 and promotes apoptosis resistance in cholangiocarcinoma
Nataliya Razumilava,Steve F. Bronk,Rory L. Smoot,Christian D. Fingas,Nathan W. Werneburg,Lewis R. Roberts,Justin L. Mott +6 more
TL;DR: Elevated miR‐25 levels in malignant cholangiocarcinoma cell lines as well as patient samples are identified and the identification of the novel TRAIL Death Receptor‐4 (DR4) provides a mechanism by which miR-25 contributes to evasion of TRAIL‐induced cholangsiocARCinoma apoptosis.
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.
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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