Glioblastoma cell-secreted interleukin-8 induces brain endothelial cell permeability via CXCR2

PLoS One. 2012;7(9):e45562. doi: 10.1371/journal.pone.0045562. Epub 2012 Sep 20.

Abstract

Glioblastoma constitutes the most aggressive and deadly of brain tumors. As yet, both conventional and molecular-based therapies have met with limited success in treatment of this cancer. Among other explanations, the heterogeneity of glioblastoma and the associated microenvironment contribute to its development, as well as resistance and recurrence in response to treatments. Increased vascularity suggests that tumor angiogenesis plays an important role in glioblastoma progression. However, the molecular crosstalk between endothelial and glioblastoma cells requires further investigation. To examine the effects of glioblastoma-derived signals on endothelial homeostasis, glioblastoma cell secretions were collected and used to treat brain endothelial cells. Here, we present evidence that the glioblastoma secretome provides pro-angiogenic signals sufficient to disrupt VE-cadherin-mediated cell-cell junctions and promote endothelial permeability in brain microvascular endothelial cells. An unbiased angiogenesis-specific antibody array screen identified the chemokine, interleukin-8, which was further demonstrated to function as a key factor involved in glioblastoma-induced permeability, mediated through its receptor CXCR2 on brain endothelia. This underappreciated interface between glioblastoma cells and associated endothelium may inspire the development of novel therapeutic strategies to induce tumor regression by preventing vascular permeability and inhibiting angiogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Brain Neoplasms / genetics
  • Brain Neoplasms / metabolism*
  • Capillary Permeability* / drug effects
  • Cell Line, Tumor
  • Culture Media, Conditioned / pharmacology
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism*
  • Gene Expression Regulation, Neoplastic
  • Glioblastoma / genetics
  • Glioblastoma / metabolism*
  • Humans
  • Interleukin-8 / metabolism*
  • Interleukin-8 / pharmacology
  • Receptors, Interleukin-8B / genetics
  • Receptors, Interleukin-8B / metabolism*

Substances

  • Culture Media, Conditioned
  • Interleukin-8
  • Receptors, Interleukin-8B

Grant support

This research was supported by Ligue Nationale contre le Cancer, Association pour la Recherche sur le Cancer (ARC), Association des Neuro Oncologues d'Expression Francaise (ANOCEF), Fondation pour la Recherche Medicale (FRM), Agence Nationale pour la Recherche (ANR JCJC) and by a Marie Curie International Reintegration grant. JD is supported by Agence Nationale pour la Recherche sur le SIDA et les hepatites virales (ANRS), EMGM and SA by Association pour la Recherche sur le Cancer (ARC), SSS by Canceropole Ile-de-France, ALG and JH by Universite Paris Descartes. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.