Cooperativity of E-cadherin and Smad4 loss to promote diffuse-type gastric adenocarcinoma and metastasis.
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 β-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 β-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 β-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.


CONCLUSIONS
This study demonstrates that inhibition of β-catenin is a converging node for the antimetastatic signaling pathways driven by E-cadherin and Smad4 in Pdx-1-Cre;Smad4(F/F);Trp53(F/F);Cdh1(F) (/+) mice, providing novel insights into mechanisms for gastric cancer metastasis.
Biomolecular Function Research Branch, National Cancer Center, Goyang, Gyeonggi; College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea;
Jun Won
JW
Park
Biomolecular Function Research Branch, National Cancer Center, Goyang, Gyeonggi;
Seok Hoon
SH
Jang
Biomolecular Function Research Branch, National Cancer Center, Goyang, Gyeonggi;
Dong Min
DM
Park
Biomolecular Function Research Branch, National Cancer Center, Goyang, Gyeonggi;
Na Jung
NJ
Lim
National Institute of Diabetes and Digestive and Kidney Diseases; and.
Chuxia
C
Deng
College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea; hkim@ncc.re.kr daeyong@snu.ac.kr jegreen@nih.gov.
Dae Yong
DY
Kim
Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, Maryland hkim@ncc.re.kr daeyong@snu.ac.kr jegreen@nih.gov.
Jeffrey E
JE
Green
Biomolecular Function Research Branch, National Cancer Center, Goyang, Gyeonggi; hkim@ncc.re.kr daeyong@snu.ac.kr jegreen@nih.gov.
Hark Kyun
HK
Kim
D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D000818:Animals; D015820:Cadherins / Q000235:genetics*; D051379:Mice; D009362:Neoplasm Metastasis / Q000235:genetics* / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics; D051901:Smad4 Protein / Q000235:genetics*; D013274:Stomach Neoplasms / Q000235:genetics / Q000473:pathology; D051176:beta Catenin / Q000235:genetics
D015820:Cadherins; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; D051176:beta Catenin