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Cancer Res. 2013 Aug 1;73(15):4909-22. doi: 10.1158/0008-5472.CAN-12-4384. Epub 2013 Jun 12.

Canonical wnt signaling is required for pancreatic carcinogenesis.

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1
Department of Surgery, University of Michigan Medical School, 1500 E Medical Center Drive, Ann Arbor, MI 48109, USA.

Abstract

Wnt ligand expression and activation of the Wnt/β-catenin pathway have been associated with pancreatic ductal adenocarcinoma, but whether Wnt activity is required for the development of pancreatic cancer has remained unclear. Here, we report the results of three different approaches to inhibit the Wnt/β-catenin pathway in a established transgenic mouse model of pancreatic cancer. First, we found that β-catenin null cells were incapable of undergoing acinar to ductal metaplasia, a process associated with development of premalignant pancreatic intraepithelial neoplasia lesions. Second, we addressed the specific role of ligand-mediated Wnt signaling through inducible expression of Dkk1, an endogenous secreted inhibitor of the canonical Wnt pathway. Finally, we targeted the Wnt pathway with OMP-18R5, a therapeutic antibody that interacts with multiple Frizzled receptors. Together, these approaches showed that ligand-mediated activation of the Wnt/β-catenin pathway is required to initiate pancreatic cancer. Moreover, they establish that Wnt signaling is also critical for progression of pancreatic cancer, a finding with potential therapeutic implications.

PMID:
23761328
PMCID:
PMC3763696
DOI:
10.1158/0008-5472.CAN-12-4384
[Indexed for MEDLINE]
Free PMC Article
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