EphB2 activity plays a pivotal role in pediatric medulloblastoma cell adhesion and invasion

AH Sikkema, WFA den Dunnen, E Hulleman, DG van Vuurden, G Garcia-Manero, H Yang, FJG Scherpen, KR Kampen, EW Hoving, WA Kamps, SH Diks, Maikel Peppelenbosch, ELSJM de Bont

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Abstract

Eph/ephrin signaling has bcen 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.
Original languageUndefined/Unknown
Pages (from-to)1125-1135
Number of pages11
JournalNeuro-Oncology
Volume14
Issue number9
DOIs
Publication statusPublished - 2012

Research programs

  • EMC MM-04-20-02-A

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