TY - JOUR
T1 - Critical role for the receptor tyrosine kinase EPHB4 in esophageal cancers
AU - Hasina, Rifat
AU - Mollberg, Nathan
AU - Kawada, Ichiro
AU - Mutreja, Karun
AU - Kanade, Geetanjali
AU - Yala, Soheil
AU - Surati, Mosmi
AU - Liu, Ren
AU - Li, Xiuqing
AU - Zhou, Yue
AU - Ferguson, Benjamin D.
AU - Nallasura, Vidya
AU - Cohen, Kenneth S.
AU - Hyjek, Elizabeth
AU - Mueller, Jeffery
AU - Kanteti, Rajani
AU - El Hashani, Essam
AU - Kane, Dorothy
AU - Shimada, Yutaka
AU - Lingen, Mark W.
AU - Husain, Aliya N.
AU - Posner, Mitchell C.
AU - Waxman, Irving
AU - Villaflor, Victoria M.
AU - Ferguson, Mark K.
AU - Varticovski, Lyuba
AU - Vokes, Everett E.
AU - Gill, Parkash
AU - Salgia, Ravi
N1 - Copyright:
Copyright 2013 Elsevier B.V., All rights reserved.
PY - 2013/1/1
Y1 - 2013/1/1
N2 - Esophageal cancer incidence is increasing and has few treatment options. In studying receptor tyrosine kinases associated with esophageal cancers, we have identi fi ed 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 signi ficantly 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 timeand 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.
AB - Esophageal cancer incidence is increasing and has few treatment options. In studying receptor tyrosine kinases associated with esophageal cancers, we have identi fi ed 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 signi ficantly 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 timeand 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.
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U2 - 10.1158/0008-5472.CAN-12-0915
DO - 10.1158/0008-5472.CAN-12-0915
M3 - Article
C2 - 23100466
AN - SCOPUS:84871962051
VL - 73
SP - 184
EP - 194
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 1
ER -