Journal ArticleDOI
Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer
D. Neil Watkins,David M. Berman,Scott G. Burkholder,Baolin Wang,Philip A. Beachy,Stephen B. Baylin +5 more
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TLDR
It is proposed that some types of SCLC might recapitulate a critical, Hh-regulated event in airway epithelial differentiation, and a common lethal malignancy that may respond to pharmacological blockade of the Hh signalling pathway is identified.Abstract:
Embryonic signalling pathways regulate progenitor cell fates in mammalian epithelial development and cancer. Prompted by the requirement for sonic hedgehog (Shh) signalling in lung development, we investigated a role for this pathway in regeneration and carcinogenesis of airway epithelium. Here we demonstrate extensive activation of the hedgehog (Hh) pathway within the airway epithelium during repair of acute airway injury. This mode of Hh signalling is characterized by the elaboration and reception of the Shh signal within the epithelial compartment, and immediately precedes neuroendocrine differentiation. We reveal a similar pattern of Hh signalling in airway development during normal differentiation of pulmonary neuroendocrine precursor cells, and in a subset of small-cell lung cancer (SCLC), a highly aggressive and frequently lethal human tumour with primitive neuroendocrine features. These tumours maintain their malignant phenotype in vitro and in vivo through ligand-dependent Hh pathway activation. We propose that some types of SCLC might recapitulate a critical, Hh-regulated event in airway epithelial differentiation. This requirement for Hh pathway activation identifies a common lethal malignancy that may respond to pharmacological blockade of the Hh signalling pathway.read more
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Wnt signalling in stem cells and cancer
Tannishtha Reya,Hans Clevers +1 more
TL;DR: Insights gained from understanding how the Wnt pathway is integrally involved in both stem cell and cancer cell maintenance and growth in the intestinal, epidermal and haematopoietic systems may serve as a paradigm for understanding the dual nature of self-renewal signals.
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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.
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Stem Cells,Cancer and Cancer Stem Cells
TL;DR: Research data show that more resistant stem cells than common cancer cells exist in cancer patients, and to identify unrecognized differences between cancer stem cells and cancer cells might be able to develop effective classification, diagnose and treat for cancer.
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
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
TL;DR: 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.
References
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Journal ArticleDOI
Stem cells, cancer, and cancer stem cells
TL;DR: Stem cell biology has come of age: Unequivocal proof that stem cells exist in the haematopoietic system has given way to the prospective isolation of several tissue-specific stem and progenitor cells, the initial delineation of their properties and expressed genetic programmes, and the beginnings of their utility in regenerative medicine.
Journal ArticleDOI
Altered Neural Cell Fates and Medulloblastoma in Mouse patched Mutants
TL;DR: The PATCHED (PTC) gene encodes a Sonic hedgehog (Shh) receptor and a tumor suppressor protein that is defective in basal cell nevus syndrome (BCNS).
Journal ArticleDOI
Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened.
TL;DR: It is shown that cyclopamine can reverse the retention of partially misfolded Smo in the endoplasmic reticulum through binding-mediated effects on protein conformation, which suggests a role for small molecules in the physiological regulation of Smo.
Journal ArticleDOI
The Hedgehog and Wnt signalling pathways in cancer
Jussi Taipale,Philip A. Beachy +1 more
TL;DR: Evidence suggesting that tumorigenesis associated with pathway activation may result from mis-specification of cells towards stem-cell or stem cell-like fates is reviewed.
Journal ArticleDOI
Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine
Jussi Taipale,James K. Chen,Michael K. Cooper,Baolin Wang,Randall K. Mann,Ljiljana Milenkovic,Matthew P. Scott,Philip A. Beachy +7 more
TL;DR: It is shown that the plant-derived teratogen cyclopamine, which inhibits the Hh response, is a potential ‘mechanism-based’ therapeutic agent for treatment of these tumours.
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