EphB4 Promotes Site-Specific Metastatic Tumor Cell Dissemination by Interacting with Endothelial Cell–Expressed EphrinB2

Abstract

The tyrosine kinase receptor EphB4 interacts with its ephrinB2 ligand to act as a bidirectional signaling system that mediates adhesion, migration, and guidance by controlling attractive and repulsive activities. Recent findings have shown that hematopoietic cells expressing EphB4 exert adhesive functions towards endothelial cells expressing ephrinB2. We therefore hypothesized that EphB4/ephrinB2 interactions may be involved in the preferential adhesion of EphB4-expressing tumor cells to ephrinB2-expressing endothelial cells. Screening of a panel of human tumor cell lines identified EphB4 expression in nearly all analyzed tumor cell lines. Human A375 melanoma cells engineered to express either full-length EphB4 or truncated EphB4 variants which lack the cytoplasmic catalytic domain (ΔC-EphB4) adhered preferentially to ephrinB2-expressing endothelial cells. Force spectroscopy by atomic force microscopy confirmed, on the single cell level, the rapid and direct adhesive interaction between EphB4 and ephrinB2. Tumor cell trafficking experiments in vivo using sensitive luciferase detection techniques revealed significantly more EphB4-expressing A375 cells but not ΔC-EphB4-expressing or mock-transduced control cells in the lungs, the liver, and the kidneys. Correspondingly, ephrinB2 expression was detected in the microvessels of these organs. The specificity of the EphB4-mediated tumor homing phenotype was validated by blocking the EphB4/ephrinB2 interaction with soluble EphB4-Fc. Taken together, these experiments identify adhesive EphB4/ephrinB2 interactions between tumor cells and endothelial cells as a mechanism for the site-specific metastatic dissemination of tumor cells. Mol Cancer Res; 8(10); 1297-309. ©2010 AACR.

Murine, but not human, ephrin-B2 can be efficiently cleaved by the serine protease kallikrein-4: Implications for xenograft models of human prostate cancer

“…However, ephrin-B2 is also present in tumours, expressed primarily on the endothelial cells of the tumour vasculature and by fibroblasts in the surrounding prostate tumour stroma [13,14]. Several groups have shown that endothelial cell ephrin-B2 plays a key role in regulating angiogenesis and lymphangiogenesis, an important element in supporting tumour growth and for arresting cells during site-specific metastatic dissemination [15][16][17]. Thus, collectively these studies suggest a fine balance and tight regulation of EphB4-ephrin-B2 interaction exists that is critical to the promotion or suppression of tumour growth and spread.…”

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

“…We believe this signaling would be further enhanced in an environment, such as bone marrow, where stroma expresses ephrinB2. Previous work has shown that tumor cells with EPHB4 expression can interact with ephrinB2 on stroma and vasculature to promote growth 30 and confer resistance to therapy. 31 Disrupting EPHB4/ephrinB2 interaction may, therefore, be a strategy to overcome treatment resistance.…”

The role of EPH receptors in cancer-related epithelial-mesenchymal transition

“…For instance, EPH receptors and their ligands can regulate stem/progenitor cell proliferation in adult tissues as well as tumor progression; this is a relevant function of EPH receptors in the context of oncology[47]. Moreover, EPH receptors can promote the dissemination of tumor cells by guiding amoeboid movement toward EPH ligands that are expressed on endothelial cells at sites of future metastatic tumor formation[48],[49]. Furthermore, natural killer cells and monocytes triggered a larger reduction in xenograft tumor volume when EPHA2 antibodies were present, suggesting that the immune system can also contribute to the function of EPH receptors in cancer[50].…”