The phosphorylation of ephrin‐B2 ligand promotes glioma cell migration and invasion
Open Access
- 2 September 2009
- journal article
- research article
- Published by Wiley in International Journal of Cancer
- Vol. 126 (5), 1155-1165
- https://doi.org/10.1002/ijc.24849
Abstract
To reveal molecular drivers of glioma invasion, two distinct glioblastoma (GBM) cell phenotypes (invading cells and tumor core cells) were collected from 19 GBM specimens using laser capture microdissection. Isolated RNA underwent whole human genome expression profiling to identify differentially expressed genes. Pathway enrichment analysis highlighted the bidirectional receptor/ligand tyrosine kinase system, EphB/ephrin‐B, as the most tightly linked system to the invading cell phenotype. Clinical relevance of ephrin‐B genes was confirmed in a clinically annotated expression data set of 195 brain biopsy specimens. Levels of ephrin‐B1 and ‐B2 mRNA were significantly higher in GBM (n = 82) than in normal brain (n = 24). Kaplan–Meier analysis demonstrated ephrin‐B2, but not ephrin‐B1, expression levels were significantly associated with short term survival in malignant astrocytomas (n = 97, p = 0.016). In human brain tumor specimens, the production and phosphorylation of ephrin‐B2 were high in GBM. Immunohistochemistry demonstrated ephrin‐B2 localization primarily in GBM cells but not in normal brain. A highly invasive glioma cell line, U87, expressed high levels of ephrin‐B2 compared with relatively less invasive cell lines. Treatment with EphB2/Fc chimera further enhanced migration and invasion of U87 cells, whereas treatment with an ephrin‐B2 blocking antibody significantly slowed migration and invasion. Forced expression of ephrin‐B2 in the U251 cell line stimulated migration and invasion in vitro and ex vivo , concomitant with tyrosine phosphorylation of ephrin‐B2. These results demonstrate that high expression of ephrin‐B2 is a strong predictor of short‐term survival and that ephrin‐B2 plays a critical role in glioma invasion rendering this signaling pathway as a potential therapeutic target.Keywords
This publication has 38 references indexed in Scilit:
- Eph–ephrin signalling in adult tissues and cancerCurrent Opinion in Cell Biology, 2008
- Eph-Ephrin Bidirectional Signaling in Physiology and DiseaseCell, 2008
- Glioma cells on the run – the migratory transcriptome of 10 human glioma cell linesBMC Genomics, 2008
- Coexpression of EphB4 and ephrinB2 in tumour advancement of ovarian cancersBritish Journal of Cancer, 2008
- ephrinB1 signals from the cell surface to the nucleus by recruitment of STAT3Proceedings of the National Academy of Sciences of the United States of America, 2007
- The C-terminus of ephrin-B1 regulates metalloproteinase secretion and invasion of cancer cellsJournal of Cell Science, 2007
- Regulation of Metastases by Signal Transducer and Activator of Transcription 3 Signaling Pathway: Clinical ImplicationsClinical Cancer Research, 2007
- Receptor Tyrosine Kinase EphB4 Is a Survival Factor in Breast CancerThe American Journal of Pathology, 2006
- Rac-dependent trans-endocytosis of ephrinBs regulates Eph–ephrin contact repulsionNature, 2003
- Mechanisms and functions of eph and ephrin signallingNature Reviews Molecular Cell Biology, 2002