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기질 세포에 의해 유도되는 위암 복막 전이에서 discoidin domain receptor 1의 역할에 대한 연구
- Alternative Title
- Inhibition of discoidin domain receptor 1 prevents stroma-induced peritoneal metastasis in gastric carcinomas
- Author(s)
- 진혜진
- Alternative Author(s)
- Hyejin Jin
- Advisor
- 허훈
- Department
- 일반대학원 의생명과학과
- Publisher
- The Graduate School, Ajou University
- Publication Year
- 2017-08
- Language
- eng
- Keyword
- Gastric carcinomas; Peritoneal metastasis; Discoidin domain receptor; Cancer-associated fibroblasts
- Alternative Abstract
- Although the interactions between cancer cells and the tumor stroma are known to play a role in the peritoneal metastasis of gastric carcinomas (GCs), effective targeting agents that block these interactions have never been reported. Discoidin domain receptor 1 (DDR1) is activated by triple-helix collagens, which are major components of tumor stroma; thus, DDR1 might have a key role in the communication between cancer cells and stroma. The aim of this study was to investigate the effect of DDR1 inhibition on stroma-induced peritoneal metastasis in GCs. Methods: We analyzed by immunohistochemistry the correlation between DDR1 expression and the pattern of recurrence in GC tissues from a cohort established in a previous study. We also co-cultured human GC cell lines with gastric cancer-associated fibroblasts (CAFs), and investigated DDR1 expression and activation by western blotting. We evaluated the CAF-induced tumorigenic ability of GC cell lines and the effects of a DDR1-specific inhibitor in organotypic cultures and a peritoneal seeding xenograft animal model. Results: The expression of DDR1 in gastric cancer tissues was significantly positively associated with early recurrence (p = 0.043) and a high incidence of peritoneal recurrence (p = 0.036). We confirmed that co-culture with CAFs elevated DDR1 protein expression in GC cell lines. CAFs also enhanced GC cell line spheroid formation in organotypic cultures in a tumor cell DDR1-dependent manner. Co-implantation of CAFs with GC cells enhanced peritoneal tumor formation in vivo, an effect that was sensitive to pharmacologic inhibition of DDR1. Conclusion: Our findings suggest that the CAF-induced elevation of DDR1 in GC cells enhances their peritoneal tumorigenesis, and that the inhibition of DDR1 signaling is an attractive strategy for the treatment of GC peritoneal metastasis.
- Fulltext
- Appears in Collections:
- Graduate School of Ajou University > Department of Biomedical Sciences > 3. Theses(Master)
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