The phosphorylation of ephrin-B2 ligand promotes glioma cell migration and invasion

Mitsutoshi Nakada, Eric M. Anderson, Tim Demuth, Satoko Nakada, Linsey B. Reavie, Kelsey L. Drake, Dominique B. Hoelzinger, Michael E. Berens

Research output: Contribution to journalArticle

59 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1155-1165
Number of pages11
JournalInternational Journal of Cancer
Volume126
Issue number5
DOIs
StatePublished - Mar 1 2010

Fingerprint

Ephrin-B2
Glioma
Cell Movement
Phosphorylation
Ligands
Glioblastoma
Ephrin-B1
Ephrins
Cell Line
Brain
Laser Capture Microdissection
Phenotype
Blocking Antibodies
Survival
Astrocytoma
Kaplan-Meier Estimate
Receptor Protein-Tyrosine Kinases
Human Genome
Brain Neoplasms
Genes

Keywords

  • Ephrin
  • Glioma
  • Invasion
  • Migration
  • Tyrosine kinase

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Nakada, M., Anderson, E. M., Demuth, T., Nakada, S., Reavie, L. B., Drake, K. L., ... Berens, M. E. (2010). The phosphorylation of ephrin-B2 ligand promotes glioma cell migration and invasion. International Journal of Cancer, 126(5), 1155-1165. https://doi.org/10.1002/ijc.24849

The phosphorylation of ephrin-B2 ligand promotes glioma cell migration and invasion. / Nakada, Mitsutoshi; Anderson, Eric M.; Demuth, Tim; Nakada, Satoko; Reavie, Linsey B.; Drake, Kelsey L.; Hoelzinger, Dominique B.; Berens, Michael E.

In: International Journal of Cancer, Vol. 126, No. 5, 01.03.2010, p. 1155-1165.

Research output: Contribution to journalArticle

Nakada, M, Anderson, EM, Demuth, T, Nakada, S, Reavie, LB, Drake, KL, Hoelzinger, DB & Berens, ME 2010, 'The phosphorylation of ephrin-B2 ligand promotes glioma cell migration and invasion', International Journal of Cancer, vol. 126, no. 5, pp. 1155-1165. https://doi.org/10.1002/ijc.24849
Nakada M, Anderson EM, Demuth T, Nakada S, Reavie LB, Drake KL et al. The phosphorylation of ephrin-B2 ligand promotes glioma cell migration and invasion. International Journal of Cancer. 2010 Mar 1;126(5):1155-1165. https://doi.org/10.1002/ijc.24849
Nakada, Mitsutoshi ; Anderson, Eric M. ; Demuth, Tim ; Nakada, Satoko ; Reavie, Linsey B. ; Drake, Kelsey L. ; Hoelzinger, Dominique B. ; Berens, Michael E. / The phosphorylation of ephrin-B2 ligand promotes glioma cell migration and invasion. In: International Journal of Cancer. 2010 ; Vol. 126, No. 5. pp. 1155-1165.
@article{5b8f7d032cc7405a8a7e8bf9b110d148,
title = "The phosphorylation of ephrin-B2 ligand promotes glioma cell migration and invasion",
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 = "Ephrin, Glioma, Invasion, Migration, Tyrosine kinase",
author = "Mitsutoshi Nakada and Anderson, {Eric M.} and Tim Demuth and Satoko Nakada and Reavie, {Linsey B.} and Drake, {Kelsey L.} and Hoelzinger, {Dominique B.} and Berens, {Michael E.}",
year = "2010",
month = "3",
day = "1",
doi = "10.1002/ijc.24849",
language = "English (US)",
volume = "126",
pages = "1155--1165",
journal = "International Journal of Cancer",
issn = "0020-7136",
publisher = "Wiley-Liss Inc.",
number = "5",

}

TY - JOUR

T1 - The phosphorylation of ephrin-B2 ligand promotes glioma cell migration and invasion

AU - Nakada, Mitsutoshi

AU - Anderson, Eric M.

AU - Demuth, Tim

AU - Nakada, Satoko

AU - Reavie, Linsey B.

AU - Drake, Kelsey L.

AU - Hoelzinger, Dominique B.

AU - Berens, Michael E.

PY - 2010/3/1

Y1 - 2010/3/1

N2 - 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.

AB - 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.

KW - Ephrin

KW - Glioma

KW - Invasion

KW - Migration

KW - Tyrosine kinase

UR - http://www.scopus.com/inward/record.url?scp=74049111863&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=74049111863&partnerID=8YFLogxK

U2 - 10.1002/ijc.24849

DO - 10.1002/ijc.24849

M3 - Article

C2 - 19728339

AN - SCOPUS:74049111863

VL - 126

SP - 1155

EP - 1165

JO - International Journal of Cancer

JF - International Journal of Cancer

SN - 0020-7136

IS - 5

ER -