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Inhibition of Discoidin Domain Receptor 1 Prevents Stroma-Induced Peritoneal Metastasis in Gastric Carcinoma

Authors
Jin, H; Ham, IH; Oh, HJ; Bae, CA; Lee, D; Kim, YB; Son, SY; Chwae, YJ; Han, SU; Brekken, RA; Hur, H
Citation
Molecular cancer research : MCR, 16(10):1590-1600, 2018
Journal Title
Molecular cancer research : MCR
ISSN
1541-77861557-3125
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.
MeSH terms
Carcinogenesis/geneticsCarcinoma/genetics*Carcinoma/pathologyCell Line, TumorCell Proliferation/geneticsDiscoidin Domain Receptor 1/genetics*Gene Expression Regulation, Neoplastic/geneticsHumansNeoplasm MetastasisNeoplasm Recurrence, Local/geneticsNeoplasm Recurrence, Local/pathologyPeritoneal Neoplasms/genetics*Peritoneal Neoplasms/pathologyPeritoneal Neoplasms/secondaryStomach Neoplasms/genetics*Stomach Neoplasms/pathology
DOI
10.1158/1541-7786.MCR-17-0710
PMID
29866925
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Surgery
Journal Papers > School of Medicine / Graduate School of Medicine > Pathology
Journal Papers > School of Medicine / Graduate School of Medicine > Microbiology
AJOU Authors
함, 인혜이, 다근김, 영배손, 상용최, 용준한, 상욱허, 훈
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