Cooperativity of E-cadherin and Smad4 Loss to Promote Diffuse-Type Gastric Adenocarcinoma and Metastasis

초록

Loss of E-cadherin (CDH1), Smad4, and p53 has been shown to play an integral role in gastric, intestinal, and breast cancer formation. Compound conditional knockout mice for Smad4, p53, and E-cadherin were generated to define and compare the roles of these genes in gastric, intestinal, and breast cancer development by crossing with Pdx-1-Cre, Villin-Cre, and MMTV-Cre transgenic mice. Interestingly, gastric adenocarcinoma was significantly more frequent in Pdx-1-Cre; Smad4(F/F); Trp53(F/F); Cdh1(F/+) mice than in Pdx-1-Cre; Smad4(F/F); Trp53(F/F); Cdh1(+/+) mice, demonstrating that Cdh1 heterozygosity accelerates the development and progression of gastric adenocarcinoma, in combination with loss of Smad4 and p53. Pdx-1-Cre; Smad4(F/F); Trp53(F/F); Cdh1(F/+) mice developed gastric adenocarcinomas without E-cadherin expression. However, intestinal and mammary adenocarcinomas with the same genetic background retained E-cadherin expression and were phenotypically similar to mice with both wild-type Cdh1 alleles. Lung metastases were identified in Pdx-1-Cre; Smad4(F/F); Trp53(F/F); Cdh1(F/+) mice, but not in the other genotypes. Nuclear beta-catenin accumulation was identified at the invasive tumor front of gastric adenocarcinomas arising in Pdx-1-Cre; Smad4(F/F); Trp53(F/F); Cdh1(F/+) mice. This phenotype was less prominent in mice with intact E-cadherin or Smad4, indicating that the inhibition of beta-catenin signaling by E-cadherin or Smad4 downregulates signaling pathways involved in metastases in Pdx-1-Cre; Smad4(F/F); Trp53(F/F); Cdh1(F/+) mice. Knockdown of beta-catenin significantly inhibited the migratory activity of Pdx-1-Cre; Smad4(F/F); Trp53(F/F); Cdh1(F/+) cell lines. Thus, loss of E-cadherin and Smad4 cooperates with p53 loss to promote the development and metastatic progression of gastric adenocarcinomas, with similarities to human gastric adenocarcinoma.

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