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

Chenzhong Kuang, Yan Xiao, Xubao Liu, Teresa M. Stringfield, Shaobo Zhang, Zhenzhen Wang, Yan Chen

Research output: Contribution to journalArticle

56 Scopus citations

Abstract

TGF-β 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-β signaling. To evaluate the in vivo function of TGF-β in the development of pancreatic cancers, we generated a transgenic mouse model with pancreas-specific expression of Smad7, a specific inhibitor of TGF-β 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-β 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.

Original languageEnglish (US)
Pages (from-to)1858-1863
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number6
DOIs
StatePublished - Feb 15 2006

Keywords

  • Fibrosis
  • Mouse model
  • Pancreatic cancer
  • Pancreatic intraepithelial neoplasia
  • Sma- and Mad-related protein 2

ASJC Scopus subject areas

  • General

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