Abstract
EphrinB2–EphB4 signaling is critical during embryogenesis for cardiovascular formation and neuronal guidance. Intriguingly, critical expression patterns have been discovered in cancer pathologies over the last two decades. Multiple connections to tumor migration, growth, angiogenesis, apoptosis, and metastasis have been identified in vitro and in vivo. However, the molecular signaling pathways are manifold and signaling of the EphB4 receptor or the ephrinB2 ligand is cancer type specific. Here we explore the impact of these signaling pathways in neurooncological disease, including glioma, brain metastasis, and spinal bone metastasis. We identify potential downstream pathways that mediate cancer suppression or progression and seek to understand it´s role in antiangiogenic therapy resistance in glioma. Despite the Janus-faced functions of ephrinB2–EphB4 signaling in cancer Eph signaling remains a promising clinical target.
Highlights
In an initial push to explore this signaling in metastatic disease we found that ephrinB2mediated EphB4 activation is crucial for repulsion of circulating melanoma cells from the spinal bone endothelium (Figure 5a) [7], despite previous evidence that the bone endothelium is a passive recipient of microbeads and cells alike [133]
Though seemingly contradictory with the notion that EphB4–ephrinB2 interaction reduces spinal metastasis formation through circulating tumor cells (CTCs) repulsion, these results indicate that both forward and reverse signaling pathways are necessary to achieve sufficient protection from extravasation and strengthen the notion that both receptor and ligand availability need to be incorporated in future analyses of ephrins and their receptors (Ephs)–ephrin signaling in metastatic disease
The ephrins and their receptors (Ephs) are major players involved in this signaling
Summary
The receptor tyrosine kinase (RTK) EphB4 and its ligand ephrinB2 are part of a larger group of signaling receptors, the Ephs, which have been shown to steer a multitude of physiological processes during adulthood and embryogenesis [1]. Activation of Eph receptors can induce cytoskeletal changes through Rho GTPases such as Rac and RhoA and in reverse signaling, Src-family kinases play a crucial role This can occur through actively induced changes in receptor expression and phosphorylation, and is further facilitated by changes within the tumor microenvironment (TME) such as increased levels of hypoxia and VEGF signaling [17,18,19]. EphrinB2 was low or undetectable in all breast cancer cell lines examined, despite the non-transformed MCF-10A human breast epithelial line [20] This indicates that the expression of the receptor and the availability and binding of ephrinB2 and the subsequent extent of kinase activation (clustering) play a pivotal role in determining proand antitumorigenic effects of EphB4 reverse signaling (Figure 1). FDA approval, are in clinical trials, or available for translational research only (Table 1)
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