Gastric and duodenal polyps in Smad4 (Dpc4) knockout mice

The SMAD4 (DPC4) gene was initially isolated as a candidate tumor suppresso r from the convergent site of homozygous deletions on 18q in a panel of pan creatic carcinoma cell lines. It encodes a common cytoplasmic signaling mol ecule shared by the transforming growth factor-p, activin, and bone morphog enic pathways. We recently inactivated its mouse homologue Smad4 and demons trated its role in the malignant progression of benign adenomas to invasive adenocarcinomas by analyzing mice with Ape and Smad4 compound mutations, A lthough simple Smad4 homozygotes were embryonically Lethal, the heterozygot es were fertile and appeared normal up to the age of 1 year. Upon further i nvestigation, however, they have developed inflammatory polyps in the gland ular stomach and duodenum, By PCR genotyping and immunohistochemical staini ng, the wild-type Smad4 allele has been lost in the polyp epithelial cells, i.e., loss of heterozygosity, On the other hand, we have not found any mut ations in such genes as K-Ras, H-Ras, N-Ras, p53, or PTEN. Histologically, the polyps are similar to human juvenile polyps showing moderate stromal ce ll proliferation and infiltrations by eosinophils and plasma cells. In addi tion, foci of adenocarcinoma with signet ring cells are also found. These r esults are consistent with a recent report that germ-line SMAD4 mutations a re found in a subset of familial juvenile polyposis.