Haploid loss of the tumor suppressor Smad4/Dpc4 initiates gastric polyposis and cancer in mice

The tumor suppressor SMAD4, also known as DPC4, deleted in pancreatic cance r, is a central mediator of TGF-P signaling. It was previously shown that m ice homozygous for a null mutation of Smad4 (Smad4(-/-)) died prior to gast rulation displaying impaired extra-embryonic membrane formation and endoder m differentiation. Here we show that Smad4(+/-) mice began to develop polyp osis in the fundus and antrum when they were over 6-12 months old, and in t he duodenum and cecum in older animals at a lower frequency, With increasin g age, polyps in the antrum show sequential changes from hyperplasia, to dy splasia, in-situ carcinoma, and finally invasion. These alterations are ini tiated by a dramatic expansion of the gastric epithelium where Smad4 is exp ressed. However, loss of the remaining Smad4 wild-type allele was detected only in later stages of tumor progression, suggesting that haploinsufficien cy of Smad4 is sufficient for tumor initiation. Our data also showed that o verexpression of TGF-beta 1 and Cyclin D1 was associated with increased pro liferation of gastric polyps and tumors. These studies demonstrate that Sma d4 functions as a tumor suppressor in the gastrointestinal tract and also p rovide a valuable model for screening factors that promote or prevent gastr ic tumorigenesis.