EphB2 activity plays a pivotal role in pediatric medulloblastoma cell adhesion and invasion.
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.
Department of Pediatric Oncology/Hematology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, Groningen, the Netherlands.
Arend H
AH
Sikkema
Wilfred F A
WF
den Dunnen
Esther
E
Hulleman
Dannis G
DG
van Vuurden
Guillermo
G
Garcia-Manero
Hui
H
Yang
Frank J G
FJ
Scherpen
Kim R
KR
Kampen
Eelco W
EW
Hoving
Willem A
WA
Kamps
Sander H
SH
Diks
Maikel P
MP
Peppelenbosch
Eveline S J M
ES
de Bont
D017209:Apoptosis; D015153:Blotting, Western; D002448:Cell Adhesion / Q000502:physiology*; D002465:Cell Movement / Q000502:physiology*; D049109:Cell Proliferation; D002528:Cerebellar Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002648:Child; D019175:DNA Methylation; D036387:Ephrin-B1 / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008527:Medulloblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D036183:Receptor, EphB2 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
D036387:Ephrin-B1; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D036183:Receptor, EphB2