Aggressive pancreatic ductal adenocarcinoma in mice caused by pancreas-specific blockade of transforming growth factor-beta signaling in cooperation with active Kras expression.
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.
Ijichi
Hideaki
H
Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee 37232, USA.
Chytil
Anna
A
Gorska
Agnieszka E
AE
Aakre
Mary E
ME
Fujitani
Yoshio
Y
Fujitani
Shuko
S
Wright
Christopher V E
CV
Moses
Harold L
HL
D000230:Adenocarcinoma / Q000473:pathology*; D000375:Aging; D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000473:pathology*; D055513:Connective Tissue Growth Factor; D018450:Disease Progression; D004848:Epithelium / Q000473:pathology; D015870:Gene Expression; D011905:Genes, ras; D006579:Heterozygote; D017874:Immediate-Early Proteins / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D009361:Neoplasm Invasiveness; D010179:Pancreas / Q000166:cytology / Q000254:growth & development / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000172:deficiency; D015398:Signal Transduction; D017154:Stromal Cells / Q000166:cytology / Q000473:pathology; D014157:Transcription Factors / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014407:Tumor Cells, Cultured
C526317:CCN2 protein, human; C526318:CCN2 protein, mouse; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D018125:Receptors, Transforming Growth Factor beta; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; C062602:transcription factor PTF1; D055513:Connective Tissue Growth Factor; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II