Crosstalk between Glioma-Initiating Cells and Endothelial Cells Drives Tumor Progression

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.

Perivascular niches as points of the utmost expression of tumor microenvironment

“…GSCs/progenitors activate endothelial cells for angiogenesis by VEGF [16] and endothelial cells keep GSC/progenitor stemness and migration capacity by Notch signaling and NO [2,5,8,17] that condition tumor progression [18]. The perivascular position of GSCs/progenitors is the consequence of the occurrence of angiogenesis in high infiltration and hyper-proliferation areas, composed mainly by GSCs/progenitors [19][20][21] and regulated by tumor microenvironment.…”

Cancer stem cells and differentiation therapy

“…The signaling activated by PDGF-NO-ID4 axis promotes tumor progression through increase in CSC self-renewal and tumor vasculature. 60 Mutations in Notch receptor activate the Notch downstream signaling pathway and transactivate gene expressions involved in stem cell signaling in a Jagged ligand-independent manner. Notch1 mutations activate Jagged/Notch signaling pathway and promote tumorigenesis in breast cancer or T-lineage acute lymphoblastic leukemia (T-ALL).…”

Effects of Gas1 on gliomas: a review on current preclinical studies

“…[20,24,25] The classification of GICs is based on the expression of prominin-1 (CD133); the CD133 + GICs are more invasive than those that do not express the antigen, and constitute 3-29% of the glioma mass. [26,27] Also, GICs from secondary cultures conserve the characteristics of the original tumor, even after several passages. [28] Self-renewal, aggressiveness and stemness of GICs are associated with the expression of Cyclin E and proteins of the family of inhibitor of DNAbinding/differentiation proteins, increased activity of several signaling pathways including: transforming growth factor (TGF)-β; protein kinase A and jagged-NOTCH; [26,29] as well as the activation of the receptors for PDGF, epidermal growth factor (EGF) and fibroblast growth factor (FGF).…”

“…[28] Self-renewal, aggressiveness and stemness of GICs are associated with the expression of Cyclin E and proteins of the family of inhibitor of DNAbinding/differentiation proteins, increased activity of several signaling pathways including: transforming growth factor (TGF)-β; protein kinase A and jagged-NOTCH; [26,29] as well as the activation of the receptors for PDGF, epidermal growth factor (EGF) and fibroblast growth factor (FGF). [26] Surprisingly, CD133…”

“…[26,28,30] It is noteworthy that CD133 + GICs are predisposed to become resistant to chemo-and radiotherapy with respect to non-GICs cells, implicating the activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2). [20,31,32] In this context, the use of classical therapies against gliomas, facilitate the selection of multi-resistant GICs, leading to the formation of more aggressive tumors, resistant to chemo-and radiotherapy.…”