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
TLDR
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.Abstract:
Hedgehog signalling--an essential pathway during embryonic pancreatic development, the misregulation of which has been implicated in several forms of cancer--may also be an important mediator in human pancreatic carcinoma. Here we report that sonic hedgehog, a secreted hedgehog ligand, is abnormally expressed in pancreatic adenocarcinoma and its precursor lesions: pancreatic intraepithelial neoplasia (PanIN). Pancreata of Pdx-Shh mice (in which Shh is misexpressed in the pancreatic endoderm) develop abnormal tubular structures, a phenocopy of human PanIN-1 and -2. Moreover, these PanIN-like lesions also contain mutations in K-ras and overexpress HER-2/neu, which are genetic mutations found early in the progression of human pancreatic cancer. Furthermore, hedgehog signalling remains active in cell lines established from primary and metastatic pancreatic adenocarcinomas. Notably, inhibition of hedgehog signalling by cyclopamine induced apoptosis and blocked proliferation in a subset of the pancreatic cancer cell lines both in vitro and in vivo. These data suggest that this pathway may have an early and critical role in the genesis of this cancer, and that maintenance of hedgehog signalling is important for aberrant proliferation and tumorigenesis.read more
Citations
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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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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
Inhibition of Hedgehog Signaling Enhances Delivery of Chemotherapy in a Mouse Model of Pancreatic Cancer
Kenneth P. Olive,Michael A. Jacobetz,Christian Davidson,Aarthi Gopinathan,Aarthi Gopinathan,Dominick J.O. McIntyre,Davina J. Honess,Basetti Madhu,Mae A. Goldgraben,Meredith E. Caldwell,David Allard,Kristopher K. Frese,Gina M. DeNicola,Gina M. DeNicola,Christine Feig,Chelsea Combs,Stephen P. Winter,Heather Ireland-Zecchini,Stefanie Reichelt,William J. Howat,Alex R. Chang,Mousumi Dhara,Lifu Wang,Lifu Wang,Felix Rückert,Robert Grützmann,Christian Pilarsky,Kamel Izeradjene,Sunil R. Hingorani,Pearl S. Huang,Susan E. Davies,William Plunkett,Merrill J. Egorin,Ralph H. Hruban,Nigel Whitebread,Karen McGovern,Julian Adams,Christine A. Iacobuzio-Donahue,John R. Griffiths,David A. Tuveson +39 more
TL;DR: Studying a mouse model of PDA that is refractory to the clinically used drug gemcitabine, it is found that the tumors in this model were poorly perfused and poorly vascularized, properties that are shared with human PDA.
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
Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma
Andrew D. Rhim,Andrew D. Rhim,Paul E. Oberstein,Dafydd H. Thomas,Emily T. Mirek,Carmine F. Palermo,Stephen A. Sastra,Erin N. Dekleva,Tyler Saunders,Claudia P. Becerra,Ian W. Tattersall,C. Benedikt Westphalen,Jan Kitajewski,Maite G. Fernandez-Barrena,Martin E. Fernandez-Zapico,Christine A. Iacobuzio-Donahue,Kenneth P. Olive,Ben Z. Stanger +17 more
TL;DR: De deleting Shh in a well-defined mouse model of PDAC demonstrated that some components of the tumor stroma can act to restrain tumor growth, and administration of VEGFR blocking antibody selectively improved survival of Shh-deficient tumors.
References
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Sonic Hedgehog Mediates the Polarizing Activity of the ZPA
TL;DR: A vertebrate gene related to the Drosophila segment polarity gene hedgehog, which is expressed specifically in the ZPA and in other regions of the embryo, that is capable of polarizing limbs in grafting experiments is isolated.
Journal ArticleDOI
Human Homolog of patched, a Candidate Gene for the Basal Cell Nevus Syndrome
Ronald L. Johnson,Alana L. Rothman,Jingwu Xie,Lisa V. Goodrich,John W. Bare,Jeannette M. Bonifas,Anthony G. Quinn,Richard M. Myers,David R. Cox,Ervin H. Epstein,Matthew P. Scott +10 more
TL;DR: Heritable mutations in BCNS patients and a somatic mutation in a sporadic BCC were identified in a human homolog of the Drosophila patched (ptc) gene, which appears to be crucial for proper embryonic development and for tumor suppression.
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.
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.
Journal ArticleDOI
Pancreatic Intraepithelial Neoplasia: A New Nomenclature and Classification System for Pancreatic Duct Lesions
Ralph H. Hruban,N V Adsay,J Albores-Saavedra,Carolyn C. Compton,E S Garrett,Steven N. Goodman,Scott E. Kern,David S. Klimstra,Günther Klöppel,Daniel S. Longnecker,Jutta Lüttges,G. J. A. Offerhaus +11 more
TL;DR: The acceptance of a standard classification system will facilitate the study of pancreatic duct lesions, and will lead ultimately to a better understanding of their biologic importance.
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