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

• Published in: Genes & development 2006-11, Vol.20 (22), p.3147-3160
• Main Authors: Ijichi, Hideaki, Chytil, Anna, Gorska, Agnieszka E, Aakre, Mary E, Fujitani, Yoshio, Fujitani, Shuko, Wright, Christopher V E, Moses, Harold L
• Format: Article
• Language: English
• Subjects: Adenocarcinoma - pathology; Aging; Animals; Carcinoma, Pancreatic Ductal - pathology; Connective Tissue Growth Factor; Disease Progression; Epithelium - pathology; Gene Expression; Genes, ras; Heterozygote; Immediate-Early Proteins - metabolism; Intercellular Signaling Peptides and Proteins - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Mutation - genetics; Neoplasm Invasiveness; Pancreas - cytology; Pancreas - growth & development; Pancreas - pathology; Pancreatic Neoplasms - pathology; Protein-Serine-Threonine Kinases; Receptors, Transforming Growth Factor beta - deficiency; Research Paper; Signal Transduction; Stromal Cells - cytology; Stromal Cells - pathology; Transcription Factors - metabolism; Transforming Growth Factor beta - metabolism; Tumor Cells, Cultured
• ISSN: 0890-9369; 1549-5477
• DOI: 10.1101/gad.1475506

Pancreatic ductal adenocarcinoma (PDAC) is an almost uniformly lethal disease in humans. Transforming growth factor-beta (TGF-beta) signaling plays an important role in PDAC progression, as indicated by the fact that Smad4, which encodes a central signal mediator downstream from TGF-beta, is deleted or mutated in 55% and the type II TGF-beta 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 (Kras(G12D)) 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 Kras(G12D) activation alone essentially generated only intraepithelial neoplasia within 1 yr. In contrast, the Tgfbr2 knockout combined with Kras(G12D) expression developed well-differentiated PDAC with 100% penetrance and a median survival of 59 d. Heterozygous deletion of Tgfbr2 with Kras(G12D) expression also developed PDAC, which indicated a haploinsufficiency of TGF-beta signaling in this genetic context. The clinical and histopathological manifestations of the combined Kras(G12D) expression and Tgfbr2 knockout mice recapitulated human PDAC. The data show that blockade of TGF-beta signaling and activated Ras signaling cooperate to promote PDAC progression.