Ionizing radiation augments glioma tropism of mesenchymal stem cells

Abstract

OBJECTIVE Mesenchymal stem cells (MSCs) have been shown to localize to gliomas after intravascular delivery. Because these cells home to areas of tissue injury, the authors hypothesized that the administration of ionizing radiation (IR) to tumor would enhance the tropism of MSCs to gliomas. Additionally, they sought to identify which radiation-induced factors might attract MSCs. METHODS To assess the effect of IR on MSC migration in vitro, transwell assays using conditioned medium (CM) from an irradiated commercially available glioma cell line (U87) and from irradiated patient-derived glioma stem-like cells (GSCs; GSC7-2 and GSC11) were employed. For in vivo testing, green fluorescent protein (GFP)-labeled MSCs were injected into the carotid artery of nude mice harboring orthotopic U87, GSC7-2, or GSC17 xenografts that were treated with either 0 or 10 Gy of IR, and brain sections were quantitatively analyzed by immunofluorescence for GFP-positive cells. These GSCs were used because GSC7-2 is a weak attractor of MSCs at baseline, whereas GSC17 is a strong attractor. To determine the factors implicated in IR-induced tropism, CM from irradiated GSC7-2 and from GSC11 was assayed with a cytokine array and quantitative ELISA. RESULTS Transwell migration assays revealed statistically significant enhanced MSC migration to CM from irradiated U87, GSC7-2, and GSC11 compared with nonirradiated controls and in a dose-dependent manner. After their intravascular delivery into nude mice harboring orthotopic gliomas, MSCs engrafted more successfully in irradiated U87 (p = 0.036), compared with nonirradiated controls. IR also significantly increased the tropism of MSCs to GSC7-2 xenografts (p = 0.043), which are known to attract MSCs only poorly at baseline (weak-attractor GSCs). Ionizing radiation also increased the engraftment of MSCs in strong-attractor GSC17 xenografts, but these increases did not reach statistical significance. The chemokine CCL2 was released by GSC7-2 and GSC11 after irradiation in a dose-dependent manner and mediated in vitro transwell migration of MSCs. Immunohistochemistry revealed increased CCL2 in irradiated GSC7-2 gliomas near the site of MSC engraftment. CONCLUSIONS Administering IR to gliomas enhances MSC localization, particularly in GSCs that attract MSCs poorly at baseline. The chemokine CCL2 appears to play a crucial role in the IR-induced tropism of MSCs to gliomas.

Enhancing the Bystander and Abscopal Effects to Improve Radiotherapy Outcomes

“…Considering all the information summarized in this review, we are convinced that, due to (i) the physical hallmarks and biological capabilities (153) that characterize neoplastic tissues, (ii) the physical-chemical tropism of MSCs (154), and (iii) the widespread functions of macromolecules, proteins, and exosomes, all these factors secreted by activated MSCs * are able to reduce pro-tumorigenic and pro-metastatic signals released by tumors that influence the progression, growth, spread, and drug resistance of tumor cells.…”

Medium-chain acyl-CoA dehydrogenase, a gatekeeper of mitochondrial function in glioblastoma multiforme

“…To achieve a functional output of metabolic gene functions that might be essential for GBM cell survival, we generated a prioritized list of 330 metabolism genes and created a barcoded, deep-coverage (10 shRNAs/gene) shRNA library that encompasses a wide range of metabolic pathways and activities ( Figure S1A). As a disease model, we selected low-passage, 3D-cultured, patient-derived glioma tumor-initiating cells (GSCs) established at the MD Anderson Brain Tumor Center (Hossain et al, 2015;Lang et al, 2018;Thomas et al, 2018). Among over 70 genomically characterized GSCs available to us, we selected two carrying distinct gene expression signatures classified as belonging to the proneural (GSC 8.11) or classical (GSC 6.27) ( Figure S1B,C) subtypes.…”

Liposomal Lapatinib in Combination with Low-Dose Photodynamic Therapy for the Treatment of Glioma

“…Patient-derived glioma stem cell lines, GSC7-2, GSC8-18, and GSC30 [31,32] were maintained as neurospheres in DMEM/F12 media supplemented with 2% B-27 supplement, 2 mM glutamine, Penicillin/Streptomycin (all Life Technologies, Carlsbad, CA, USA), 10 ng/mL EGF (Sigma-Aldrich, Oakville, ON, CAN), 10 ng/mL basic FGF (R&D Systems, Minneapolis, MN, USA). When spheres reached 100 µm in diameter, they were dissociated for passaging or for experiments using a combination of Accutase (Corning Life Sciences, Tewksbury, MA, USA) and trituration.…”