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 kinase-activity 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.