CXCL12 mediates trophic interactions between endothelial and tumor cells in glioblastoma

Shyam Rao, Rajarshi Sengupta, Eun Joo Choe, B. Mark Woerner, Erin Jackson, Tao Sun, Jeffrey Leonard, David Piwnica-Worms, Joshua B. Rubin

Research output: Contribution to journalArticle

43 Scopus citations

Abstract

Emerging evidence suggests endothelial cells (EC) play a critical role in promoting Glioblastoma multiforme (GBM) cell proliferation and resistance to therapy. The molecular basis for GBM-EC interactions is incompletely understood. We hypothesized that the chemokine CXCL12 and its receptor CXCR4 could mediate direct interactions between GBM cells and tumor-associated endothelial cells and that disruption of this interaction might be the molecular basis for the anti-tumor effects of CXCR4 antagonists. We investigated this possibility in vivo and in an in vitro co-culture model that incorporated extracellular matrix, primary human brain microvascular ECs (HBMECs) and either an established GBM cell line or primary GBM specimens. Depletion of CXCR4 in U87 GBM cells blocked their growth as intracranial xenografts indicating that tumor cell CXCR4 is required for tumor growth in vivo. In vitro, co-culture of either U87 cells or primary GBM cells with HBMECs resulted in their co-localization and enhanced GBM cell growth. Genetic manipulation of CXCL12 expression and pharmacological inhibition of its receptors CXCR4 and CXCR7 revealed that the localizing and trophic effects of endothelial cells on GBM cells were dependent upon CXCL12 and CXCR4. These findings indicate that the CXCL12/CXCR4 pathway directly mediates endothelial cell trophic function in GBMs and that inhibition of CXCL12-CXCR4 signaling may uniquely target this activity. Therapeutic disruption of endothelial cell trophic functions could complement the structural disruption of anti-angiogenic regimens and, in combination, might also improve the efficacy of radiation and chemotherapy in treating GBMs.

Original languageEnglish (US)
Article numbere33005
JournalPLoS One
Volume7
Issue number3
DOIs
StatePublished - Mar 12 2012
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

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    Rao, S., Sengupta, R., Choe, E. J., Woerner, B. M., Jackson, E., Sun, T., Leonard, J., Piwnica-Worms, D., & Rubin, J. B. (2012). CXCL12 mediates trophic interactions between endothelial and tumor cells in glioblastoma. PLoS One, 7(3), [e33005]. https://doi.org/10.1371/journal.pone.0033005