Abstract
Discoidin domain receptor 1 (DDR1) is activated by fibrillar (triple-helical) collagens and collagen IV, which are major components of tumor stroma; thus, DDR1 might be a critical mediator of 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 gastric carcinoma. We analyzed by immunohistochemistry the correlation between DDR1 expression and the pattern of recurrence in gastric carcinoma tissues from a previously characterized and established gastric carcinoma patient cohort. We also cocultured human gastric carcinoma cell lines with gastric cancer-associated fibroblasts (CAF) and investigated DDR1 expression and activation. We evaluated CAF-induced tumorigenic properties of gastric carcinoma cell lines and the effect of a DDR1-specific inhibitor in organotypic cultures and in a peritoneal seeding xenograft animal model. The expression of DDR1 in gastric cancer tissues was positively associated with early recurrence (P = 0.043) and a high incidence of peritoneal recurrence (P = 0.036). We confirmed that coculturing with CAFs elevated DDR1 protein expression in gastric carcinoma cell lines and enhanced gastric carcinoma cell line spheroid formation in organotypic cultures in a tumor cell DDR1-dependent manner. Coimplantation of CAFs with gastric carcinoma cells enhanced peritoneal tumor formation in vivo, an effect that was sensitive to pharmacologic inhibition of DDR1.Implications: This study highlights that CAF-induced elevation of DDR1 expression in gastric carcinoma cells enhances peritoneal tumorigenesis, and that inhibition of DDR1 is an attractive strategy for the treatment of gastric carcinoma peritoneal metastasis. Mol Cancer Res; 16(10); 1590-600. ©2018 AACR.
Highlights
Gastric carcinoma is one of the most common malignant tumors and the third leading cause of cancer-related deaths worldwide [1]
Gene set enrichment analysis (GSEA) was used to determine potentially altered signaling pathways and the results identified that the IL6/JAK/STAT3 signaling-related genes were enriched in MKN74 cells cocultured with cancer– associated fibroblasts (CAF) [enrichment score: 1.83, nominal P < 0.001, false discovery rate (FDR) Q 1⁄4 0.001, family wise error rare (FWER) P 1⁄4 0.006; Supplementary Fig. S3C]
This study reveals the potential of Discoidin domain receptor 1 (DDR1) as a novel therapeutic target to prevent stroma-induced gastric carcinoma peritoneal recurrence after resection
Summary
Gastric carcinoma is one of the most common malignant tumors and the third leading cause of cancer-related deaths worldwide [1]. Mortality from gastric carcinoma has gradually decreased in recent years, patients with latestage disease still have poor prognosis due to tumor nonresectability or recurrence after resection. Large-scale clinical trials showed that adjuvant chemotherapy following curative resection could reduce the recurrence rate of stage II or III gastric carcinoma. Patients enrolled in those trials suffered recurrence during the follow-up period, and the peritoneum is one of the most common sites of recurrence [2, 3]. Specific modalities to prevent gastric carcinoma peritoneal metastases have not been established. New strategies based on specific molecular biomarkers related to peritoneal metastasis must be developed to prevent gastric carcinoma peritoneal recurrence
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