@article{b1ea057e9b974b7cb83ee35ac09f25c6,
title = "Stabilization of β-Catenin Induces Pancreas Tumor Formation",
abstract = "Background & Aims: β-Catenin signaling within the canonical Wnt pathway is essential for pancreas development. However, the pathway is normally down-regulated in the adult organ. Increased cytoplasmic and nuclear localization of β-catenin can be detected in nearly all human solid pseudopapillary neoplasms (SPN), a rare tumor with low malignant potential. Conversely, pancreatic ductal adenocarcinoma (PDA) accounts for the majority of pancreatic tumors and is among the leading causes of cancer death. Whereas activating mutations within β-catenin and other members of the canonical Wnt pathway are rare, recent reports have implicated Wnt signaling in the development and progression of human PDA. Here, we sought to address the role of β-catenin signaling in pancreas tumorigenesis. Methods: Using Cre/lox technology, we conditionally activated β-catenin in a subset of murine pancreatic cells in vivo. Results: Activation of β-catenin results in the formation of large pancreatic tumors at a high frequency in adult mice. These tumors resemble human SPN based on morphologic and immunohistochemical comparisons. Interestingly, stabilization of β-catenin blocks the formation of pancreatic intraepithelial neoplasia (PanIN) in the presence of an activating mutation in Kras that is known to predispose individuals to PDA. Instead, mice in which β-catenin and Kras are concurrently activated develop distinct ductal neoplasms that do not resemble PanIN lesions. Conclusions: These results demonstrate that activation of β-catenin is sufficient to induce pancreas tumorigenesis. Moreover, they indicate that the sequence in which oncogenic mutations are acquired has profound consequences on the phenotype of the resulting tumor.",
author = "Heiser, {Patrick W.} and Cano, {David A.} and Limor Landsman and Kim, {Grace E.} and Kench, {James G.} and Klimstra, {David S.} and Taketo, {Maketo M.} and Biankin, {Andrew V.} and Matthias Hebrok",
note = "Funding Information: The authors are indebted to Drs Doug Melton, Chris Wright, Sunil Hingorani, and David Tuveson for providing the Pdx-Cre early , Ptf1a-Cre mouse strains, and Kras G12D , respectively, and to Dr Mike German for providing the Pdx1 antibody. We also thank Drs Mike German and Gail Martin for helpful discussions, Jane Milliken for help with the human SPN immunohistochemistry, Micah Allen for histology support, Heather Heiser for the maintenance of our mouse stocks, and Don and Marcia Trask for imaging assistance. Work in M.H.'s laboratory was supported by grants from the NIH (CA112537, DK60533) and the American Diabetes Association. P.W.H. was a part of the UCSF Biomedical Science graduate student program when this research was conducted. D.A.C. was supported by a postdoctoral fellowship from the California Institute of Regenerative Medicine (CIRM). L.L. was supported by a postdoctoral fellowship from the Juvenile Diabetes Research Foundation. Confocal and other images were generated in the UCSF Diabetes and Endocrinology Research Center microscopy core (P30 DK63720). ",
year = "2008",
month = oct,
doi = "10.1053/j.gastro.2008.06.089",
language = "אנגלית",
volume = "135",
pages = "1288--1300",
journal = "Gastroenterology",
issn = "0016-5085",
publisher = "W.B. Saunders",
number = "4",
}