Aggressive pancreatic ductal adenocarcinoma in mice caused by pancreas-specific blockade of transforming growth factor-beta signaling in cooperation with active Kras expression

作者：Ijichi Hideaki; Chytil Anna; Gorska Agnieszka E; Aakre Mary E; Fujitani Yoshio; Fujitani Shuko; Wright Christopher V E; Moses Harold L

来源：Genes & Development, 2006, 20(22): 3147-3160.

DOI：10.1101/gad.1475506

<jats:p>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 <jats:italic>Smad4</jats:italic>, which encodes a central signal mediator downstream from TGF-β, is deleted or mutated in 55% and the <jats:italic>type II TGF-β receptor</jats:italic> (<jats:italic>Tgfbr2</jats:italic>) gene is altered in a smaller subset of human PDAC. Pancreas-specific <jats:italic>Tgfbr2</jats:italic> knockout mice have been generated, alone or in the context of active <jats:italic>Kras</jats:italic> (<jats:italic>Kras<jats:sup>G12D</jats:sup></jats:italic>) expression, using the Cre-loxP system driven by the endogenous <jats:italic>Ptf1a</jats:italic> (<jats:italic>pancreatic transcription factor-1a</jats:italic>) locus. Pancreas-selective <jats:italic>Tgfbr2</jats:italic> knockout alone gave no discernable phenotype in 1.5 yr. Pancreas-specific <jats:italic>Kras<jats:sup>G12D</jats:sup></jats:italic> activation alone essentially generated only intraepithelial neoplasia within 1 yr. In contrast, the <jats:italic>Tgfbr2</jats:italic> knockout combined with <jats:italic>Kras<jats:sup>G12D</jats:sup></jats:italic> expression developed well-differentiated PDAC with 100% penetrance and a median survival of 59 d. Heterozygous deletion of <jats:italic>Tgfbr2</jats:italic> with <jats:italic>Kras<jats:sup>G12D</jats:sup></jats:italic> expression also developed PDAC, which indicated a haploinsufficiency of TGF-β signaling in this genetic context. The clinical and histopathological manifestations of the combined <jats:italic>Kras<jats:sup>G12D</jats:sup></jats:italic> expression and <jats:italic>Tgfbr2</jats:italic> knockout mice recapitulated human PDAC. The data show that blockade of TGF-β signaling and activated Ras signaling cooperate to promote PDAC progression.</jats:p>

• 出版日期2006-11-15