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 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. Cancer Res; 73(1); 184-94. Ó2012 AACR.

KSR1 and EPHB4 Regulate Myc and PGC1β To Promote Survival of Human Colon Tumors

“…Our laboratory has recently shown that KSR1 also promotes anchorageindependent growth and tumor maintenance in human colon tumor cell lines (16 (16,19,44,45), the similarity of siKSR1-and siEPHB4-dependent gene expression signatures suggests that EPHB4 is likely to support colon tumor cell survival similarly to KSR1. EPHB4 expression is elevated in a variety of human cancers, including cancers of the head and neck, prostate, bladder, ovaries, large intestine, lung, brain, pancreas, and esophagus (46)(47)(48)(49)(50)(51)(52)(53)(54). We analyzed the expression of EPHB4 in a panel of colon tumor cells compared to its expression in HCECs.…”

“…The mechanistic role that EPHB4 plays in cancer remains controversial. However, a preponderance of data indicate that EPHB4 is overexpressed broadly in human cancers, including cancers of the head and neck, prostate, bladder, ovaries, large intestine, lung, brain, pancreas, and esophagus (46)(47)(48)(49)(50)(51)(52)(53)(54). Further research has shown that the ablation or inhibition of EPHB4 in a number of cancer cell types reduces tumor cell viability, including prostate (47), bladder (48), ovarian (49), colon (50), lung (51), head and neck squamous cell carcinoma (74), and esophageal (54) cancer.…”

Clinical Significance of EphB4 and EphB6 Expression in Human Malignant and Benign Thyroid Lesions

“…Notably, EphB4 inhibition reduced cellular viability, in vitro, halted the growth of established tumors in mouse xenograft models, in vivo, and caused near-complete regression of established tumours in combination with paclitaxel in lung cancer [41]. Specific smallmolecule EphB4 inhibitor decreased cell viability in a timeand dose-dependent manner in esophageal cancer cell lines [42]. The above small-molecule inhibitor and an EphB4 siRNA also decreased cell migration, with decreased phosphorylation of various tyrosyl-containing proteins, including EphB4 and its downstream target p125FAK [42].…”

“…Specific smallmolecule EphB4 inhibitor decreased cell viability in a timeand dose-dependent manner in esophageal cancer cell lines [42]. The above small-molecule inhibitor and an EphB4 siRNA also decreased cell migration, with decreased phosphorylation of various tyrosyl-containing proteins, including EphB4 and its downstream target p125FAK [42]. In a xenograft tumor model of esophageal cancer, EphB4 inhibition abrogated tumor growth by approximately 60 % compared to untreated control [42].…”

EPHB4 is a therapeutic target in AML and promotes leukemia cell survival via AKT

“…8 In esophageal tumors, the EPHB4 gene appears amplified and contributes to tumor cell survival and migration. 9 Expression of EPHB4 was associated with clinically aggressive disease in gastric and gastroesophageal junction tumors. 10 In colorectal cancer, EPHB4 was shown to not only promote tumor growth, but also tumor-associated angiogenesis.…”