Crosstalk between glioma-initiating cells and endothelial cells drives tumor progression

Hye Min Jeon, Sung Hak Kim, Xun Jin, Jong Bae Park, Se Hoon Kim, Kaushal Joshi, Ichiro Nakano, Hyunggee Kim

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Abstract

Glioma-initiating cells (GIC), which reside within the perivascular microenvironment to maintain self-renewal capacity, are responsible for glioblastoma initiation, progression, and recurrence. However, the molecular mechanisms controlling crosstalk between GICs and endothelial cells are poorly understood. Here, we report that, in both GICs and endothelial cells, platelet-derived growth factor (PDGF)-driven activation of nitric oxide (NO) synthase increases NO-dependent inhibitor of differentiation 4 (ID4) expression, which in turn promotes JAGGED1-NOTCH activity through suppression of miR129 that specifically represses JAGGED1 suppression. This signaling axis promotes tumor progression along with increased GIC self-renewal and growth of tumor vasculature in the xenograft tumors, which is dramatically suppressed by NOTCH inhibitor. ID4 levels correlate positively with NOS2 (NO synthase-2), HES1, and HEY1 and negatively with miR129 in primary GICs. Thus, targeting the PDGF-NOS-ID4-miR129 axis and NOTCH activity in the perivascular microenvironment might serve as an efficacious therapeutic modality for glioblastoma.

Original languageEnglish
Pages (from-to)4482-4492
Number of pages11
JournalCancer Research
Volume74
Issue number16
DOIs
Publication statusPublished - 2014 Aug 15

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All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Jeon, H. M., Kim, S. H., Jin, X., Park, J. B., Kim, S. H., Joshi, K., Nakano, I., & Kim, H. (2014). Crosstalk between glioma-initiating cells and endothelial cells drives tumor progression. Cancer Research, 74(16), 4482-4492. https://doi.org/10.1158/0008-5472.CAN-13-1597