Genomic landscape of a mouse model of diffuse-type gastric adenocarcinoma

Abstract Background There is a need for a model of diffuse-type gastric cancer that captures the features of the disease, facilitates the study of its mechanisms, and aids the development of potential therapies. One such model may be Cdh1 and Trp53 double conditional knockout (DCKO) mice, which have histopathological features similar to those of human diffuse-type gastric cancer. However, a genomic profile of this mouse model has yet to be completed. Methods Whole-genome sequences of tumors from eight DCKO mice were analyzed and their molecular features were compared with those of human gastric adenocarcinoma. Results DCKO mice gastric cancers harbored single nucleotide variations and indel patterns comparable to those of human genomically stable gastric cancers, whereas their copy number variation fraction and ploidy were more similar to human chromosomal instability gastric cancers (perhaps due to Trp53 knockout). Copy number variations dominated changes in cancer-related genes in DCKO mice, with typical high-level amplifications observed for oncogenic drivers, e.g., Myc, Ccnd1, and Cdks, as well as gastrointestinal transcription factors, e.g., Gata4, Foxa1, and Sox9. Interestingly, frequent alterations in gastrointestinal transcription factors in DCKO mice indicated their potential role in tumorigenesis. Furthermore, mouse gastric cancer had a reproducible but smaller number of mutational signatures than human gastric cancer, including the potentially acid-related signature 17, indicating shared tumorigenic etiologies in humans and mice. Conclusions Cdh1/Trp53 DCKO mice have similar genomic features to those found in human gastric cancer; hence, this is a suitable model for further studies of diffuse-type gastric cancer mechanisms and therapies.

Download Full-text

Relationship of novel genetically engineered mouse and the epithelial-mesenchymal transition in the metastastic progression of gastric cancers.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.3_suppl.3 ◽

2014 ◽

Vol 32 (3_suppl) ◽

pp. 3-3

Author(s):

Hark K. Kim ◽

Jun Won Park ◽

Jeffrey E. Green

Keyword(s):

Gastric Cancer ◽

Lung Metastases ◽

Genetically Engineered ◽

Conditional Knockout ◽

Metastatic Progression ◽

Diffuse Type ◽

Mesenchymal Transition ◽

Gastric Cancers ◽

Gastric Adenocarcinomas ◽

E Cadherin

3 Background: By creating mice deficient in E-cadherin, Smad4, and p53, we evaluated whether and how Cdh1 heterozygosity may accelerate the development and progression of gastric cancer, in combination with loss of Smad4 and p53. Methods: Compound conditional knockout mice of Smad4, p53, and E-cadherin were mated with Pdx-1-Cre transgenic mice. Offsprings were monitored for the development of gastric adenocarcinomas. Results: Gastric adenocarcinomas spontaneously arose in Pdx-1-Cre;Smad4F/F;Trp53F/F;Cdh1F/+ mice and recapitulated human diffuse type gastric cancers in histopathology. Gastric adenocarcinoma was more frequent in Pdx-1-Cre;Smad4F/F;Trp53F/F;Cdh1F/+ mice than in Pdx-1-Cre;Smad4F/F;Trp53F/F mice. When compared to Pdx-1-Cre;Trp53F/F;Cdh1F/F mice, Pdx-1-Cre;Smad4F/F;Trp53F/F;Cdh1F/+ mice developed gastric adenocarcinomas more rapidly, suggesting that Smad4 and E-cadherin cooperate to constrain the development of gastric adenocarcinomas. Lung metastases were identified in three Pdx-1-Cre;Smad4F/F;Trp53F/F;Cdh1F/+ mice, but not in the other genotypes. The epithelial-to-mesenchymal transition (EMT), characterized by increased vimentin expression, was identified at the invasive tumor front of gastric adenocarcinomas arising in Pdx-1-Cre;Smad4F/F;Trp53F/F;Cdh1F/+ mice. This phenotype was less prominent in mice with intact E-cadherin or Smad4, indicating that the suppression of EMT by E-cadherin or Smad4 may reduce metastatic signaling pathways in Pdx-1-Cre;Smad4F/F;Trp53F/F;Cdh1F/+ mice. Conclusions: Loss of E-cadherin and Smad4 cooperate with p53 loss to promote the development and metastatic progression of gastric adenocarcinomas, with similarities to human diffuse type gastric cancer. Thus, our novel genetically-engineered mouse models reveal the importance of EMT in the metastatic progression of gastric cancers, providing a unique model to test agents targeting the metastatic progression in gastric cancers.

Download Full-text

Circulating microRNAs as biomarkers for early detection of diffuse-type gastric cancer using a mouse model

British Journal of Cancer ◽

10.1038/bjc.2013.30 ◽

2013 ◽

Vol 108 (4) ◽

pp. 932-940 ◽

Cited By ~ 37

Author(s):

P Rotkrua ◽

S Shimada ◽

K Mogushi ◽

Y Akiyama ◽

H Tanaka ◽

...

Keyword(s):

Gastric Cancer ◽

Early Detection ◽

Mouse Model ◽

Diffuse Type ◽

Circulating Micrornas ◽

Diffuse Type Gastric Cancer

Download Full-text

Asporin Expression on Stromal Cells and/or Cancer Cells Might Be A Useful Prognostic Marker in Patients with Diffuse-Type Gastric Cancer

European Surgical Research ◽

10.1159/000515458 ◽

2021 ◽

pp. 1-8

Author(s):

Masakazu Yashiro ◽

Tsuyoshi Hasegawa ◽

Yurie Yamamoto ◽

Gen Tsujio ◽

Sadaaki Nishimura ◽

...

Keyword(s):

Gastric Cancer ◽

Overall Survival ◽

Cancer Cells ◽

Prognostic Marker ◽

Cancer Progression ◽

Stromal Cells ◽

Intestinal Type ◽

Human Gastric Cancer ◽

Diffuse Type ◽

Diffuse Type Gastric Cancer

Background: Asporin (ASPN), a member of the proteoglycan family, has been shown to have a close correlation with cancer progression. It is not known whether ASPN is an oncogenic driver or a tumor suppressor in human gastric cancer. We sought herein to determine the relationship between ASPN expression and clinicopathological features of gastric cancer. Patients and Methods: A total of 296 gastric cancer patients (diffuse type, n = 144; intestinal type, n = 152) were enrolled. The ASPN expression level in each case was analyzed by immunohistochemistry. Results: ASPN was mainly found on stromal cells, especially on fibroblasts in tumor stroma, i.e., cancer-associated fibroblasts. The ASPN expression on either cancer cells or stromal cells was significantly high in macroscopic scirrhous-type tumors (p < 0.001) and histologically abundant stroma-type tumors (p < 0.001). Interestingly, a Kaplan-Meier survival curve of the 144 cases of diffuse-type gastric cancer revealed a significantly poorer prognosis in patients with ASPN-positive expression (p = 0.043; log rank) compared to those with ASPN-negative expression, but the prognoses were not significantly different in these subgroups of the 152 cases of intestinal-type gastric cancer. A multivariate analysis with respect to overall survival showed that ASPN expression on stromal cells and/or cancer cells was significantly correlated with overall survival in patients with diffuse-type gastric cancer (p = 0.041). Conclusion: In gastric cancer, ASPN was expressed mainly on stromal cells and partially on cancer cells. ASPN expression on stromal cells and/or cancer cells might be a useful prognostic marker in patients with diffuse-type gastric cancer.

Download Full-text