Inhibition of Notch Signaling in Glioblastoma Targets Cancer Stem Cells via an Endothelial Cell Intermediate

Abstract

Glioblastoma multiforme (GBM) is a highly heterogeneous malignant tumor. Recent data suggests the presence of a hierarchical organization within the GBM cell population that involves cancer cells with stem-like behavior, capable of repopulating the tumor and contributing to its resistance to therapy. Tumor stem cells are thought to reside within a vascular niche that provides structural and functional support. However, most GBM studies involve isolated tumor cells grown under various culture conditions. Here, we use a novel three-dimensional organotypic “explant” system of surgical GBM specimens that preserves cytoarchitecture and tumor stroma along with tumor cells. Notch inhibition in explants results in decreased proliferation and self-renewal of tumor cells but is also associated with a decrease in endothelial cells. When endothelial cells are selectively eliminated from the explants via a toxin conjugate, we also observed a decrease in self-renewal of tumor stem cells. These findings support a critical role for tumor endothelial cells in GBM stem cell maintenance, mediated at least in part by Notch signaling. The explant system further highlighted differences in the response to radiation between explants and isolated tumor neurospheres. Combination treatment with Notch blockade and radiation resulted in a substantial decrease in proliferation and in self-renewal in tumor explants while radiation alone was less effective. This data suggests that the Notch pathway plays a critical role in linking angiogenesis and cancer stem cell self-renewal and is thus a potential therapeutic target. Three-dimensional explant systems provide a novel approach for the study of tumor and microenvironment interactions.

Multiplexed RNAi therapy against brain tumor-initiating cells via lipopolymeric nanoparticle infusion delays glioblastoma progression

“…Indeed, the biodistribution study of the 7C1 LPNPs used for our study indicates negligible presence in the brain tissue (23). However, with the recent recognition of perivascular niches for BTIC invasive growth (11,(44)(45)(46)(47), direct in vivo RNAi delivery via nano vehicles with vasculature affinity may increase the retention and therapeutic efficacy of BTIC-targeting siRNAs in the tumor microenvironment by minimizing off-target distribution. Based on patient data published in the IVY Glioblastoma Atlas Project (IVY GAP; glioblastoma.…”

“…It builds on the blood vessel-targeting capacity of the customizable 7C1 lipopolymeric nano vehicle, which has excellent safety profiles (14,15,23,70). The 7C1 delivery system ensures dual strength in direct delivery to the tumor cellular core (where the great majority of BTICs reside) and vasculature-associated invasive niches (11,(44)(45)(46)(47) (where residual resistant populations of BTICs accumulate after a standard therapy regimen). Additionally, we maintained continuous focused delivery via a CED brain-infusion catheter that is undergoing clinical trials for both malignant brain tumors and neurodegenerative diseases (71)(72)(73)(74).…”

c-Jun N-terminal kinase has a pivotal role in the maintenance of self-renewal and tumorigenicity in glioma stem-like cells

“…52 In a similar way, glioma stem-like cells are localized in a perivascular region, in which Notch signaling is triggered by binding of transmembrane ligands on endothelial cells to Notch receptors on glioma cells. 53 However, Notch signaling in glioma stem-like cells in their niche also appears to be regulated by other distinctive mechanisms. Recently, Eyler et al 54 found that proliferation of glioma stem-like cells is facilitated by nitrogen oxide (NO), whereas the increase of NO had no effect on cell growth of normal neural stem cells.…”

Targeting therapy-resistant cancer stem cells by hyperthermia

“…They secrete nitric oxide, activating the Notch signalling pathway [132] which controls cell fate, self-renewal, angiogenesis and endothelium interactions in the CSC microenvironment. In glioblastoma, the Notch signalling causes radioresistance in CSCs [133] and inhibition of this pathway or angiogenesis can deplete the CSC population [134,135]. Furthermore, fibroblasts that inhabit the tumour microenvironment are essential for cell proliferation and for promotion of angiogenesis [136].…”