Aggressive pancreatic ductal adenocarcinoma in mice caused by pancreas-specific blockade of transforming growth factor-β signaling in cooperation with active Kras expression
- Hideaki Ijichi1,
- Anna Chytil1,4,
- Agnieszka E. Gorska1,4,
- Mary E. Aakre1,4,
- Yoshio Fujitani2,3,5,
- Shuko Fujitani2,3,6,
- Christopher V.E. Wright2,3, and
- Harold L. Moses1,4,7
- 1 Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee 37232, USA;
- 2 Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee 37232, USA;
- 3 Vanderbilt University Program in Developmental Biology, Vanderbilt University, Nashville, Tennessee 37232, USA;
- 4 The Vanderbilt-Ingram Comprehensive Cancer Center, Vanderbilt University, Nashville, Tennessee 37232, USA
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an almost uniformly lethal disease in humans. Transforming growth factor-β (TGF-β) signaling plays an important role in PDAC progression, as indicated by the fact that Smad4, which encodes a central signal mediator downstream from TGF-β, is deleted or mutated in 55% and the type II TGF-β receptor (Tgfbr2) gene is altered in a smaller subset of human PDAC. Pancreas-specific Tgfbr2 knockout mice have been generated, alone or in the context of active Kras (KrasG12D) expression, using the Cre-loxP system driven by the endogenous Ptf1a (pancreatic transcription factor-1a) locus. Pancreas-selective Tgfbr2 knockout alone gave no discernable phenotype in 1.5 yr. Pancreas-specific KrasG12D activation alone essentially generated only intraepithelial neoplasia within 1 yr. In contrast, the Tgfbr2 knockout combined with KrasG12D expression developed well-differentiated PDAC with 100% penetrance and a median survival of 59 d. Heterozygous deletion of Tgfbr2 with KrasG12D expression also developed PDAC, which indicated a haploinsufficiency of TGF-β signaling in this genetic context. The clinical and histopathological manifestations of the combined KrasG12D expression and Tgfbr2 knockout mice recapitulated human PDAC. The data show that blockade of TGF-β signaling and activated Ras signaling cooperate to promote PDAC progression.
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Footnotes
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↵7 Corresponding author.
↵7 E-MAIL hal.moses{at}vanderbilt.edu; FAX (615) 936-1790.
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Supplemental material is available at http://www.genesdev.org.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/NA
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- Received July 28, 2006.
- Accepted September 27, 2006.
- Copyright © 2006, Cold Spring Harbor Laboratory Press