Ephrin-B2 Overexpression Enhances Integrin-Mediated ECM-attachment and Migration of B16 Melanoma Cells

Int J Oncol. 2005 Nov;27(5):1197-206.

Abstract

Eph-receptor tyrosine kinases (Eph-RTKs) and their membrane-bound receptor-like ligands, the ephrins, represent a cell-cell signaling system that directs cellular migration during development. Differential expression in cancer suggests similar roles in tumor progression. We have previously shown that ephrin-B2 mRNA is overexpressed in advanced malignant melanomas (MM). In this study, immunohistochemistry revealed a most prominent expression of ephrin-B2 in the invasive front of advanced MM. Therefore, we addressed the question of whether ephrin-B2 signaling modulates MM cell migration and matrix interaction. Using a wild-type ephrin-B2-negative B16 mouse MM subclone we show that overexpression of ephrin-B2 leads to the formation of multiple lamellipodia, enhanced polymerisation of actin fibers, and induction of focal adhesion complexes with constitutive activation of focal adhesion kinase. Consequently, ephrin-B2-overexpressing B16 cells display a significant increase of beta1-integrin-mediated attachment to matrix components, preferentially laminin and fibronectin. As a further effect of ephrin-B2 overexpression, we observed an accelerated migration in both Boyden chamber invasion experiments as well as in in vitro scratch-wound assays. We conclude that ephrin-B2 can act as a major modulator of cell migration and matrix interactions of MM cells, which possibly contributes to the expansion and metastatic spread of MM in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Adhesion
  • Cell Movement
  • Ephrin-B2 / biosynthesis*
  • Extracellular Matrix / physiology*
  • Gene Expression Profiling
  • Melanoma / pathology*
  • Mice
  • Neoplasm Invasiveness
  • Neoplasm Metastasis / physiopathology
  • Pseudopodia / physiology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Skin Neoplasms / pathology*

Substances

  • Ephrin-B2