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
Tumour stem cells and drug resistance
TL;DR: Gaining a better insight into the mechanisms of stem-cell resistance to chemotherapy might lead to new therapeutic targets and better anticancer strategies.
Journal ArticleDOI
Identification of Pancreatic Cancer Stem Cells
Chenwei Li,David G. Heidt,Piero Dalerba,Charles F. Burant,Lanjing Zhang,Volkan Adsay,Max S. Wicha,Michael F. Clarke,Diane M. Simeone +8 more
TL;DR: This work identified a highly tumorigenic subpopulation of pancreatic cancer cells expressing the cell surface markers CD44, CD24, and epithelial-specific antigen (ESA) that showed the stem cell properties of self-renewal, the ability to produce differentiated progeny, and increased expression of the developmental signaling molecule sonic hedgehog.
Journal ArticleDOI
Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice
Sunil R. Hingorani,Lifu Wang,Asha S. Multani,Chelsea Combs,Therese B. Deramaudt,Ralph H. Hruban,Anil K. Rustgi,Sandy Chang,David A. Tuveson +8 more
TL;DR: Targeted concomitant endogenous expression of Trp53(R172H) and Kras(G12D) to the mouse pancreas reveals the cooperative development of invasive and widely metastatic carcinoma that recapitulates the human disease.
Journal ArticleDOI
Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis
Sarah P. Thayer,Marina Pasca di Magliano,Patrick W. Heiser,Corinne M. Nielsen,Drucilla J. Roberts,Gregory Y. Lauwers,Yan Ping Qi,Stephan Gysin,Carlos Fernandez-del Castillo,Vijay Yajnik,Bozena Antoniu,Martin McMahon,Andrew L. Warshaw,Matthias Hebrok +13 more
TL;DR: It is reported that sonic hedgehog, a secreted hedgehog ligand, is abnormally expressed in pancreatic adenocarcinoma and its precursor lesions: pancreatic intraepithelial neoplasia (PanIN), and that maintenance of hedgehog signalling is important for aberrant proliferation and tumorigenesis.
Journal ArticleDOI
The mechanisms of Hedgehog signalling and its roles in development and disease.
TL;DR: Novel biological insights are revealed into the function of HH lipidation in the secretion and transport of this ligand and details of the signal transduction pathway, which involves Patched 1, Smoothened and GLI proteins, as well as, in vertebrates, primary cilia.
References
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Journal ArticleDOI
Osteoblasts and The Hematopoietic Microenvironment.
TL;DR: It is hypothesize that osteoblasts play a critical role in hematopoietic cells development in vivo and synthesize multiple cytokines believed to regulate hematoiesis.
Journal ArticleDOI
Epidemiologic and etiologic factors of pancreatic cancer
TL;DR: High-risk groups include blacks, men, smokers, and patients with certain preexisting diseases such as pancreatitis and long-standing diabetes, which increase the risk of pancreatic cancer.
Book ChapterDOI
Turning mesoderm into blood: the formation of hematopoietic stem cells during embryogenesis.
Alan J. Davidson,Leonard I. Zon +1 more
TL;DR: Key determinants of hematopoietic fate include the product of the zebrafish cloche gene and the basic helix-loop-helix transcription factor SCL and future studies should reveal other critical factors in this developmental pathway.
Journal ArticleDOI
Helicobacter pylori strain-specific modulation of gastric mucosal cellular turnover: implications for carcinogenesis.
Richard M. Peek,Richard M. Peek +1 more
TL;DR: The combination of increased proliferation without a concordant increase in apoptosis may contribute to the heightened retention of mutagenized cells, which over decades may increase the subsequent risk for gastric cancer.
Journal ArticleDOI
The relative spatial distribution of in vitro‐CFCs in the bone marrow, responding to specific growth factors
TL;DR: Results corroborate earlier data which indicate a developmental movement of cells from the centre of the marrow tissue towards the bone surface and back again, sequentially encountering a series of growth factors which promote their differentiation into mature cells, for release at the central venous sinus.
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