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Updated: Feb 13, 2026
Establishment of Gastric Cancer Patient-derived Xenograft Models and Primary Cell Lines
Published on: July 19, 2019
Identification of selective inhibitors for diffuse-type gastric cancer cells by screening of annotated compounds in
Shu Shimada1, Yoshimitsu Akiyama2, Kaoru Mogushi2,3
1Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan. shimada.monc@tmd.ac.jp.
Background:
Diffuse-type gastric cancer (DGC) exhibits rapid disease progression and poor patient prognosis. We have previously established an E-cadherin/p53 double conditional knockout (DCKO) mouse line as the first genetically engineered one, which morphologically and molecularly recapitulates human DGC. In this study, we explored low-molecular-weight drugs selectively eliminating mouse and human DGC cells.
Methods:
We derived mouse gastric cancer (GC) cell lines from DGC of the DCKO mice demonstrating enhanced tumourigenic activity in immunodeficient mice and acquired tolerance to cytotoxic anti-cancer agents.
Results:
We performed a synthetic lethal screening of 1535 annotated chemical compounds, and identified 27 candidates selectively killing the GC cell lines. The most potent drug mestranol, an oestrogen derivative, and other oestrogen receptor modulators specifically attenuated cell viability of the GC cell lines by inducing apoptosis preceded by DNA damage. Moreover, mestranol could significantly suppress tumour growth of the GC cells subcutaneously transplanted into nude mice, consistent with longer survival time in the female DCKO mice than in the male. Expectedly, human E-cadherin-mutant and -low gastric cancer cells showed higher susceptibility to oestrogen drugs in contrast to E-cadherin-intact ones in vitro and in vivo.
Conclusions:
These findings may lead to the development of novel therapeutic strategies targeting DGC.
Insights
Researchers explored drugs to treat diffuse-type gastric cancer (DGC). Mestranol and other estrogen drugs effectively reduced DGC cell viability and tumor growth in mice, offering new therapeutic possibilities.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Diffuse-type gastric cancer (DGC) is aggressive with poor outcomes.
- A novel E-cadherin/p53 double conditional knockout (DCKO) mouse model accurately mimics human DGC.
- This study investigates targeted therapies for DGC.
Purpose of the Study:
- To identify low-molecular-weight drugs that selectively eliminate mouse and human DGC cells.
- To evaluate the efficacy of identified drugs in preclinical models.
- To explore potential therapeutic strategies for DGC.
Main Methods:
- Derived mouse gastric cancer (GC) cell lines from DGC DCKO mice.
- Performed synthetic lethal screening of 1535 chemical compounds.
- Assessed drug efficacy in vitro and in vivo using mouse models and human cell lines.
Main Results:
- Identified 27 drug candidates selectively killing GC cell lines.
- Mestranol, an estrogen derivative, and other estrogen receptor modulators induced apoptosis and DNA damage in GC cells.
- Mestranol suppressed tumor growth in mice, and estrogen drugs were more effective against E-cadherin-mutant/low human gastric cancer cells.
Conclusions:
- Estrogen receptor modulators show promise as targeted therapies for DGC.
- Findings support the development of novel therapeutic strategies for DGC.
- The study highlights the potential of targeting E-cadherin status in gastric cancer treatment.
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