In vivo disruption of TGF-β signaling by Smad7 leads to premalignant ductal lesions in the pancreas

Abstract

TGF-␤ has been postulated to play an important role in the development of pancreatic cancers. More than 50% of human pancreatic cancers bear mutations of Sma-and Mad-related protein (Smad) 4, a critical protein required for TGF-␤ signaling. To evaluate the in vivo function of TGF-␤ in the development of pancreatic cancers, we generated a transgenic mouse model with pancreas-specific expression of Smad7, a specific inhibitor of TGF-␤ signaling. Through the use of elastase I promoter, we directed the tissue specific expression of exogenous Smad7. Consistently, the exogenous Smad7 was detected only in the pancreas in the transgenic mice, and, furthermore, phosphorylation of Smad2 was blocked in the pancreatic tissues. At 6 months of age, most transgenic animals developed premalignant ductal lesions in the pancreas, with characteristics of pancreatic intraepithelial neoplasia (PanIN), a precursor to invasive pancreatic cancers. The premalignant lesions of the pancreas were accompanied by accelerated proliferation of the ductal epithelium and acinar cells, as well as increased fibrosis around the ductal lesions. This study not only demonstrated that in vivo inactivation of TGF-␤ signaling is implicated in the development of early stage of pancreatic cancers, but also provided a promising animal model useful for the investigation and intervention of pancreatic cancers in humans.mouse model ͉ pancreatic cancer ͉ pancreatic intraepithelial neoplasia ͉ fibrosis ͉ Sma-and Mad-related protein 2

Hypoxic Conversion of SMAD7 Function from an Inhibitor into a Promoter of Cell Invasion

“…Somewhat contradictory to this is that Smad7 is known to be upregulated in several carcinomas (28)(29)(30)(31)(32). Moreover, targeted overexpression of Smad7 has been reported to promote tumor growth, supporting a beneficial rather than inhibitory role in cancer progression (20,21,28,29,31,48,49). Here, we confirm the inhibitory effect of Smad7 on invasion under normoxic conditions and show upregulation of Smad7 in HNSCC.…”

SPSB1, a Novel Negative Regulator of the Transforming Growth Factor-β Signaling Pathway Targeting the Type II Receptor

“…For instance, deletion of one copy of the Smad4 or TGF-␤1 gene resulted in gastric tumor formation in mice (6,7). Similarly, overexpression of a dominant negative form of T␤RII or the negative regulator Smad7 as a transgene in mice also resulted in tumor formation (8,9). This suggests that a complete blocking of the TGF-␤ signaling is not necessary for tumor formation.…”

“…For instance, deletion of one copy of the Smad4 or TGF-␤1 gene resulted in gastric tumor formation (6,7). Similarly, overexpression of a dominant negative form of TGF-␤ type II receptor (T␤RII) 2 or the negative regulator Smad7 as a transgene in mice also resulted in tumor formation (8,9), suggesting that complete blocking of the TGF-␤ signaling is not necessary for tumor formation. More recently, the threshold effect of TGF-␤ signaling in cancer development has been further demonstrated in Gp130 Y757F/ϩ ; Smad3 ϩ/Ϫ compound mice (10), with Gp130 Y757F/ϩ heterozygous mice desensitized to TGF-␤ signaling (ϳ30%) via Stat3-mediated Smad7 expression and Smad3 ϩ/Ϫ mice showing ϳ30% reduction in TGF-␤ signaling (10).…”

Tumor-stroma interactions in pancreatic ductal adenocarcinoma

“…At age 6 months, most of the transgenic mice developed PanIN, which were accompanied by increased proliferation of the ductal cells and acinar cells and an increased fibrosis around the ductal lesions (39). This study shows that in vivo inactivation of TGFh signaling pathway leads to the development of premalignant pancreatic lesions and provides a promising animal model for molecular dissection of this pathway and a model for early therapeutic intervention.…”