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Inhibiting the GAS6/AXL axis suppresses stroma-induced progression in gastric carcinoma
- Alternative Title
- Cheong A Bae
- Author(s)
- 배청아
- Alternative Author(s)
- Cheong A Bae
- Advisor
- 허훈
- Department
- 일반대학원 의생명과학과
- Publisher
- The Graduate School, Ajou University
- Publication Year
- 2019-02
- Language
- eng
- Alternative Abstract
- Introduction: Cancer-associated fibroblasts (CAFs) are a major component of tumor stroma and their effect on the progression of gastric carcinoma (GC) has recently been demonstrated. However, agents targeting the interaction between CAFs and GC cells have not been applied in a clinical setting. Growth arrest-specific 6 (GAS6) is a major ligand of AXL receptor tyrosine kinase (AXL) and its binding is essential for activation of AXL. In the present study, we found that, in the GC microenvironment, GAS6 mainly originates from CAFs. Thus, AXL might have a key role in the communication between cancer cells and CAFs. The aim of this study was to investigate the effect of an AXL inhibitor on CAF-induced GC progression. Methods: We examined GAS6 and AXL expression in various cell lines, including GC cells and non-cancerous cells, by qRT-PCR and western blotting. We also co-cultured human GC cells with CAFs and investigated phosphorylation of AXL by western blotting and immunocytochemistry. We evaluated the role of CAF-derived GAS6 on the motility, proliferation, and tumorigenic ability of GC cells. The effect of the AXL-specific inhibitor, BGB324, on the CAF-induced aggressive phenotype of GC cells was also investigated. Finally, we performed immunohistochemistry to measure the phosphorylation of AXL in a tissue microarray composed of 175 GC tissues, and evaluated its correlation with the prognosis of GC patients. Results: qRT-PCR and western blotting showed that GAS6 expression was higher in CAFs relative to other cells. We found that CAFs increased the phosphorylation of AXL, differentiation into a mesenchymal-like phenotype, and proliferation in GC cells. Co-implantation of CAFs with GC cells enhanced peritoneal tumor formation in vivo. When the expression of AXL was inhibited in GC cells, the effect of CAF was reduced. In addition, BGB324, a small molecule inhibitor of AXL, suppressed the effects of CAFs on GC cells. In GC tissues, a high level of phosphorylated AXL were significantly associated with poor overall survival (P = 0.022). Conclusion: Above findings indicated that the CAF-induced activation of AXL in GC cells was significantly associated with poor prognosis of GC patients. We conclude that an AXL inhibitor may be a novel agent for GC treatment.
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- Graduate School of Ajou University > Department of Biomedical Sciences > 3. Theses(Master)
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