title: Discoidin domain receptor 1 activity drives an aggressive phenotype in gastric carcinoma.
abstract: Discoidin domain receptor 1 (DDR1), a receptor tyrosine kinase that utilizes collagen as a ligand, is a key molecule in the progression of solid tumors as it regulates the interaction of cancer cells with the tumor stroma. However, the clinical relevance of DDR1 expression in gastric carcinoma is yet to be investigated. Here, we assessed the role of DDR1 in mediating the aggressive phenotype of gastric carcinoma and its potential as a therapeutic target.
  
  
  
  We conducted DDR1 immunohistochemistry using a tissue microarray of 202 gastric carcinoma specimens. We examined the effect of collagen-induced activation of DDR1 on cell signaling, tumorigenesis, and cell migration in gastric cancer cell lines, and tumor growth in a xenograft animal model of gastric cancer.
  
  
  
  Our results showed that 50.5% of gastric cancer tissues are positive for DDR1 expression, and positive DDR1 expression was significantly correlated with a poor prognosis (P = 0.015). In a subgroup analysis, DDR1 expression was prognostically meaningful only in patients receiving adjuvant treatment (P = 0.013). We also demonstrated that collagen was able to activate DDR1 and increase the clonogenicity and migration of gastric cancer cells. We observed that a DDR1 inhibitor, 7rh benzamide, suppressed tumor growth in gastric cancer xenografts.
  
  
  
  Our findings suggest a key role for DDR1 signaling in mediating the aggressive phenotype of gastric carcinoma. Importantly, inhibition of DDR1 is an attractive strategy for gastric carcinoma therapy.
authors.affiliation: Division of Gastrointestinal Surgery, Department of Surgery, Ajou University School of Medicine, 164 Worldcup-ro, Yeongtong-gu, Suwon, 443-380, South Korea. hhcmc75@naver.com.|Brain Korea 21 Plus Research Center for Biomedical Sciences, Ajou University, Suwon, Korea. hhcmc75@naver.com.|Division of Surgical Oncology, Department of Surgery, Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX, 75390-8593, USA. hhcmc75@naver.com.
authors.forename: Hoon
authors.identifier: 0000-0002-5435-5363
authors.initials: H
authors.lastname: Hur
authors.affiliation: Division of Gastrointestinal Surgery, Department of Surgery, Ajou University School of Medicine, 164 Worldcup-ro, Yeongtong-gu, Suwon, 443-380, South Korea.|Brain Korea 21 Plus Research Center for Biomedical Sciences, Ajou University, Suwon, Korea.
authors.forename: In-Hye
authors.initials: IH
authors.lastname: Ham
authors.affiliation: Department of Pathology, Ajou University School of Medicine, Suwon, Korea.
authors.forename: Dakeun
authors.initials: D
authors.lastname: Lee
authors.affiliation: Division of Gastrointestinal Surgery, Department of Surgery, Ajou University School of Medicine, 164 Worldcup-ro, Yeongtong-gu, Suwon, 443-380, South Korea.|Brain Korea 21 Plus Research Center for Biomedical Sciences, Ajou University, Suwon, Korea.
authors.forename: Hyejin
authors.initials: H
authors.lastname: Jin
authors.affiliation: Division of Surgical Oncology, Department of Surgery, Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX, 75390-8593, USA.
authors.forename: Kristina Y
authors.initials: KY
authors.lastname: Aguilera
authors.affiliation: Division of Gastrointestinal Surgery, Department of Surgery, Ajou University School of Medicine, 164 Worldcup-ro, Yeongtong-gu, Suwon, 443-380, South Korea.
authors.forename: Hye Jeong
authors.initials: HJ
authors.lastname: Oh
authors.affiliation: Division of Gastrointestinal Surgery, Department of Surgery, Ajou University School of Medicine, 164 Worldcup-ro, Yeongtong-gu, Suwon, 443-380, South Korea.
authors.forename: Sang-Uk
authors.initials: SU
authors.lastname: Han
authors.affiliation: Department of Pathology, Ajou University School of Medicine, Suwon, Korea.
authors.forename: Ji Eun
authors.initials: JE
authors.lastname: Kwon
authors.affiliation: Department of Pathology, Ajou University School of Medicine, Suwon, Korea.
authors.forename: Young-Bae
authors.initials: YB
authors.lastname: Kim
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Ding
authors.affiliation: Division of Surgical Oncology, Department of Surgery, Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX, 75390-8593, USA. Rolf.Brekken@utsouthwestern.edu.
authors.forename: Rolf A
authors.initials: RA
authors.lastname: Brekken
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics / Q000473:pathology; D002277:Carcinoma / Q000235:genetics* / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D003094:Collagen / Q000378:metabolism; D000070819:Discoidin Domain Receptor 1 / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010641:Phenotype; D011379:Prognosis; D015398:Signal Transduction / Q000235:genetics; D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology*
chemical_list: D003094:Collagen; D000070819:Discoidin Domain Receptor 1
keywords: Cancer stroma; Discoidin domain receptor 1; Gastric carcinoma; Prognosis