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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Mouse models of pancreatic cancer: the fur is finally flying!
TL;DR: Progress in mouse models allows the evaluation of novel strategies for early detection, chemoprevention, and therapy and also provides new insights regarding the potential for differentiated and undifferentiated cell types to act as cells of origin for pancreatic ductal adenocarcinoma.
Journal ArticleDOI
Tumor-Suppressor Function of SPARC-Like Protein 1/Hevin in Pancreatic Cancer
Irene Esposito,Hany Kayed,Shereen Keleg,Thomas Giese,E. Helene Sage,Peter Schirmacher,Helmut Friess,Jörg Kleeff +7 more
TL;DR: Its anti-invasive effects and reduced expression in metastasis indicate tumor-suppressor function, and SPARCL1 expression in pancreatic tissues is highly correlated with level of vascularity.
Journal ArticleDOI
A Polymeric Nanoparticle Encapsulated Small Molecule Inhibitor of Hedgehog Signaling (NanoHHI) Bypasses Secondary Mutational Resistance to Smoothened Antagonists
Venugopal Chenna,Chaoxin Hu,Dipankar Pramanik,Blake T. Aftab,Collins Karikari,Nathaniel R. Campbell,Seung-Mo Hong,Ming Zhao,Michelle A. Rudek,Saeed R. Khan,Saeed R. Khan,Charles M. Rudin,Anirban Maitra +12 more
TL;DR: NanoHHI should be amenable to clinical translation in settings where tumors acquire mutational resistance to current Smo antagonists, and significantly impedes the growth of orthotopic Pa03C pancreatic cancer xenografts that have a ligand-dependent, paracrine mechanism of Hh activation when compared with gemcitabine alone.
Journal ArticleDOI
Cooperative integration between HEDGEHOG-GLI signalling and other oncogenic pathways: implications for cancer therapy
Silvia Pandolfi,Barbara Stecca +1 more
TL;DR: Recent findings on the cooperative integration of HH-GLI signalling with the major oncogenic inputs are reviewed and how these cues modulate the activity of the GLI proteins in cancer are discussed.
Journal ArticleDOI
Hedgehog signaling pathway mediates the progression of non-invasive breast cancer to invasive breast cancer
Masae Souzaki,Makoto Kubo,Masaya Kai,Chizu Kameda,Haruo Tanaka,Tomoaki Taguchi,Masao Tanaka,Hideya Onishi,Mitsuo Katano +8 more
TL;DR: The Hh pathway mediates progression from a non‐invasive phenotype to an invasive phenotype and %Gli1 nuclear translocation may be useful as a predictive marker for evaluating the ability of invasiveness.
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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