Eph/ephrin signaling has been implicated in various types of key cancer-enhancing processes, like migration, proliferation, and angiogenesis. In medulloblastoma, invading tumor cells characteristically lead to early recurrence and a decreased prognosis. Based on kinaseactivity profiling data published recently, we hypothesized a key role for the Eph/ephrin signaling system in medulloblastoma invasion. In primary medulloblastoma samples, a significantly higher expression of EphB2 and the ligand ephrin-B1 was observed compared with normal cerebellum. Furthermore, medulloblastoma cell lines showed high expression of EphA2, EphB2, and EphB4. Stimulation of medulloblastoma cells with ephrin-B1 resulted in a marked decrease in in vitro cell adhesion and an increase in the invasion capacity of cells expressing high levels of EphB2. The cell lines that showed an ephrin-B1-induced phenotype possessed increased levels of phosphorylated EphB2 and, to a lesser extent, EphB4 after stimulation. Knockdown of EphB2 expression by short hairpin RNA completely abolished ephrin ligand-induced effects on adhesion and migration. Analysis of signal transduction identified p38, Erk, and mTOR as downstream signaling mediators potentially inducing the ephrin-B1 phenotype. In conclusion, the observed deregulation of Eph/ephrin expression in medulloblastoma enhances the invasive phenotype, suggesting a potential role in local tumor cell invasion and the formation of metastases.

Adhesion, Eph, EphB2, Ephrin-B1, Invasion, Medulloblastoma
dx.doi.org/10.1093/neuonc/nos130, hdl.handle.net/1765/63866
Neuro-Oncology
Department of Gastroenterology & Hepatology

Sikkema, A.H, den Dunnen, W.F.A, Hulleman, E, van Vuurden, D.G, Garcia-Manero, G, Yang, H, … de Bont, E.S.J.M. (2012). EphB2 activity plays a pivotal role in pediatric medulloblastoma cell adhesion and invasion. Neuro-Oncology, 14(9), 1125–1135. doi:10.1093/neuonc/nos130