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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A Randomized Phase II Trial of Vismodegib versus Placebo with FOLFOX or FOLFIRI and Bevacizumab in Patients with Previously Untreated Metastatic Colorectal Cancer
Jordan Berlin,Johanna C. Bendell,Lowell L. Hart,Irfan Firdaus,Ira Gore,Robert C. Hermann,Mary F. Mulcahy,Mark M. Zalupski,Howard Mackey,Robert L. Yauch,Richard A. Graham,Gordon L Bray,Jennifer A. Low +12 more
TL;DR: Compared with placebo, treatment intensity was lower for all regimen components in vismodegib-treated patients, suggesting that combined toxicity may have contributed to lack of efficacy.
Journal ArticleDOI
Constitutive Hedgehog Signaling in Chondrosarcoma Up-Regulates Tumor Cell Proliferation
Tri Dung Tiet,Sevan Hopyan,Puviindran Nadesan,Nalan Gokgoz,Raymond Poon,Alvin C. Lin,Taiqiang Yan,Irene L. Andrulis,Benjamin A. Alman,Jay S. Wunder +9 more
TL;DR: The data raise the intriguing possibility that Hedgehog blockade could serve as an effective treatment for chondrosarcoma, a tumor for which there are currently no universally effective nonsurgical management options.
Journal ArticleDOI
DYRK1B-dependent autocrine-to-paracrine shift of Hedgehog signaling by mutant RAS
Matthias Lauth,Åsa Bergström,Takashi Shimokawa,Ulrica Tostar,Qianren Jin,Volker Fendrich,Carmen Guerra,Mariano Barbacid,Rune Toftgård +8 more
TL;DR: The molecular cross-talk between RAS and HH signaling is investigated and it is found that, although mutant RAS induces or enhances SHH expression and favors paracrine HH signaling, it antagonizes autocrine HH signal transduction.
Journal ArticleDOI
Targeting medulloblastoma: small-molecule inhibitors of the Sonic Hedgehog pathway as potential cancer therapeutics.
Justyna T. Romer,Tom Curran +1 more
TL;DR: It is shown that a small-molecule inhibitor of this pathway can regress tumors that arise in a transgenic mouse model of medulloblastoma, suggesting that inhibitors of Sonic Hedgehog signaling may offer an effective way to target some malignancies.
Journal ArticleDOI
Prospective identification of a multilineage progenitor in murine stomach epithelium.
Xiaotan T. Qiao,Joshua W. Ziel,Wendy McKimpson,Blair B. Madison,Andrea Todisco,Juanita L. Merchant,Linda C. Samuelson,Deborah L. Gumucio +7 more
TL;DR: It is shown that these rare epithelial cells are normally quiescent, but multiply in response to interferon gamma, and lineage tracing studies confirm that these cells give rise to all gastric lineages of the antral glands.
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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