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

다국어 초록 (Multilingual Abstract)

<P>Loss of E-cadherin (<I>CDH1</I>), 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 <I>Pdx-1-Cre</I>, <I>Villin-Cre</I>, and <I>MMTV-Cre</I> transgenic mice. Interestingly, gastric adenocarcinoma was significantly more frequent in <I>Pdx-1-Cre;Smad4<SUP>F/F</SUP>;Trp53<SUP>F/F</SUP>;Cdh1<SUP>F</SUP></I><SUP>/+</SUP> mice than in <I>Pdx-1-Cre;Smad4<SUP>F/F</SUP>;Trp53<SUP>F/F</SUP>;Cdh1</I><SUP>+/+</SUP> mice, demonstrating that <I>Cdh1</I> heterozygosity accelerates the development and progression of gastric adenocarcinoma, in combination with loss of Smad4 and p53. <I>Pdx-1-Cre;Smad4<SUP>F/F</SUP>;Trp53<SUP>F/F</SUP>;Cdh1<SUP>F</SUP></I><SUP>/+</SUP> 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 <I>Cdh1</I> alleles. Lung metastases were identified in <I>Pdx-1-Cre;Smad4<SUP>F/F</SUP>;Trp53<SUP>F/F</SUP>;Cdh1<SUP>F</SUP></I><SUP>/+</SUP> mice, but not in the other genotypes. Nuclear β-catenin accumulation was identified at the invasive tumor front of gastric adenocarcinomas arising in <I>Pdx-1-Cre;Smad4<SUP>F/F</SUP>;Trp53<SUP>F/F</SUP>;Cdh1<SUP>F</SUP></I><SUP>/+</SUP> mice. This phenotype was less prominent in mice with intact E-cadherin or Smad4, indicating that the inhibition of β-catenin signaling by E-cadherin or Smad4 downregulates signaling pathways involved in metastases in <I>Pdx-1-Cre;Smad4<SUP>F/F</SUP>;Trp53<SUP>F/F</SUP>;Cdh1<SUP>F</SUP></I><SUP>/+</SUP> mice. Knockdown of β-catenin significantly inhibited the migratory activity of <I>Pdx-1-Cre;Smad4<SUP>F/F</SUP>;Trp53<SUP>F/F</SUP>;Cdh1<SUP>F</SUP></I><SUP>/+</SUP> 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.</P><P><B>Implications:</B> This study demonstrates that inhibition of β-catenin is a converging node for the antimetastatic signaling pathways driven by E-cadherin and Smad4 in <I>Pdx-1-Cre;Smad4<SUP>F/F</SUP>;Trp53<SUP>F/F</SUP>;Cdh1<SUP>F</SUP></I><SUP>/+</SUP> mice, providing novel insights into mechanisms for gastric cancer metastasis. <I>Mol Cancer Res; 12(8); 1088–99. ©2014 AACR</I>.</P>