title: Critical role for the receptor tyrosine kinase EPHB4 in esophageal cancers.
abstract: Esophageal cancer incidence is increasing and has few treatment options. In studying receptor tyrosine kinases associated with esophageal cancers, we have identified EPHB4 to be robustly overexpressed in cell lines and primary tumor tissues. In total, 94 squamous cell carcinoma, 82 adenocarcinoma, 25 dysplasia, 13 Barrett esophagus, and 25 adjacent or unrelated normal esophageal tissues were evaluated by immunohistochemistry. EPHB4 expression was significantly higher in all the different histologic categories than in adjacent normal tissues. In 13 esophageal cancer cell lines, 3 of the 9 SCC cell lines and 2 of the 4 adenocarcinomas expressed very high levels of EPHB4. An increased gene copy number ranging from 4 to 20 copies was identified in a subset of the overexpressing patient samples and cell lines. We have developed a novel 4-nitroquinoline 1-oxide (4-NQO)-induced mouse model of esophageal cancer that recapitulates the EPHB4 expression in humans. A specific small-molecule inhibitor of EPHB4 decreased cell viability in a time- and dose-dependent manner in 3 of the 4 cell lines tested. The small-molecule inhibitor and an EPHB4 siRNA also decreased cell migration (12%-40% closure in treated vs. 60%-80% in untreated), with decreased phosphorylation of various tyrosyl-containing proteins, EphB4, and its downstream target p125FAK. Finally, in a xenograft tumor model, an EPHB4 inhibitor abrogated tumor growth by approximately 60% compared with untreated control. EphB4 is robustly expressed and potentially serves as a novel biomarker for targeted therapy in esophageal cancers.
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, Departments of Pathology and Surgery, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Rifat
authors.initials: R
authors.lastname: Hasina
authors.forename: Nathan
authors.initials: N
authors.lastname: Mollberg
authors.forename: Ichiro
authors.initials: I
authors.lastname: Kawada
authors.forename: Karun
authors.initials: K
authors.lastname: Mutreja
authors.forename: Geetanjali
authors.initials: G
authors.lastname: Kanade
authors.forename: Soheil
authors.initials: S
authors.lastname: Yala
authors.forename: Mosmi
authors.initials: M
authors.lastname: Surati
authors.forename: Ren
authors.initials: R
authors.lastname: Liu
authors.forename: Xiuqing
authors.initials: X
authors.lastname: Li
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhou
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Ferguson
authors.forename: Vidya
authors.initials: V
authors.lastname: Nallasura
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Cohen
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Hyjek
authors.forename: Jeffery
authors.initials: J
authors.lastname: Mueller
authors.forename: Rajani
authors.initials: R
authors.lastname: Kanteti
authors.forename: Essam
authors.initials: E
authors.lastname: El Hashani
authors.forename: Dorothy
authors.initials: D
authors.lastname: Kane
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Shimada
authors.forename: Mark W
authors.initials: MW
authors.lastname: Lingen
authors.forename: Aliya N
authors.initials: AN
authors.lastname: Husain
authors.forename: Mitchell C
authors.initials: MC
authors.lastname: Posner
authors.forename: Irving
authors.initials: I
authors.lastname: Waxman
authors.forename: Victoria M
authors.initials: VM
authors.lastname: Villaflor
authors.forename: Mark K
authors.initials: MK
authors.lastname: Ferguson
authors.forename: Lyuba
authors.initials: L
authors.lastname: Varticovski
authors.forename: Everett E
authors.initials: EE
authors.lastname: Vokes
authors.forename: Parkash
authors.initials: P
authors.lastname: Gill
authors.forename: Ravi
authors.initials: R
authors.lastname: Salgia
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology; D000818:Animals; D001471:Barrett Esophagus / Q000201:enzymology; D014408:Biomarkers, Tumor / Q000032:analysis*; D002294:Carcinoma, Squamous Cell / Q000201:enzymology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004938:Esophageal Neoplasms / Q000201:enzymology*; D018628:Gene Dosage; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D051379:Mice; D060888:Real-Time Polymerase Chain Reaction; D036224:Receptor, EphB4 / Q000032:analysis / Q000096:biosynthesis*; D046888:Tissue Array Analysis; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; D036224:Receptor, EphB4