Abstract
Abstract Introduction: Discoidin domain receptor-1 (DDR1), a receptor tyrosine kinase, is expressed by about 50% of gastric tumor cells in previous our study and is activated by fibrillar collagens, which are major components of tumor stroma. Further, it has been proposed that peritoneal metastasis is associated with high stroma content in gastric carcinomas (GCs). In this study we investigated the contribution of DDR1 activity to peritoneal metastasis of GCs. Methods: We performed the immunohistochemistry for DDR1 and Masson’s trichrome staining for accumulation of collagen bundles in 202 human GC tissues. The human GC cell lines (MKN-28 and KATO-III) were co-cultured with GCs-associated fibroblasts (CAFs), and the expression of DDR1 and signal transduction pathways were investigated by Western blot. We evaluated CAF-induced tumorigenesis of GCs cell lines and the effects of DDR1 specific inhibitor in 3D co-culture system and peritoneal seeding in xenograft animal models. Results: High stromal collagen correlated with peritoneal recurrence (P=0.004) and was positively associated with expression of DDR1 in GC tissues (P<0.001). We confirmed that co-culture with CAFs elevated the expression of DDR1 in GC cell lines. CAFs also enhanced GC cell line spheroid formation in vitro 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 CAF-induced elevation of tumor cells DDR1 enhances peritoneal tumorigenesis of GCs and the inhibition of DDR1 signaling is an attractive strategy for the treatment of GC peritoneal metastasis. Citation Format: Hyejin Jin, In-Hye Ham, Hye Jung Oh, Dakeun Lee, Sang-Uk Han, Rolf A. Brekken, Hoon Hur. Stroma-induced up-regulation of discoidin domain receptor 1 enhances peritoneal metastasis of gastric carcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-216. doi:10.1158/1538-7445.AM2017-LB-216
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