title: 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.
authors.affiliation: Departments of1Neurosurgery and.|3Department of Neurosurgery, Baylor College of Medicine; and.
authors.forename: Jonathan G
authors.initials: JG
authors.lastname: Thomas
authors.affiliation: Departments of1Neurosurgery and.|4Department of Bioengineering, Rice University, Houston, Texas.
authors.forename: Brittany C
authors.initials: BC
authors.lastname: Parker Kerrigan
authors.affiliation: Departments of1Neurosurgery and.
authors.forename: Anwar
authors.initials: A
authors.lastname: Hossain
authors.affiliation: Departments of1Neurosurgery and.
authors.forename: Joy
authors.initials: J
authors.lastname: Gumin
authors.affiliation: Departments of1Neurosurgery and.
authors.forename: Naoki
authors.initials: N
authors.lastname: Shinojima
authors.affiliation: Departments of1Neurosurgery and.
authors.forename: Felix
authors.initials: F
authors.lastname: Nwajei
authors.affiliation: 2Radiation Oncology, The University of Texas MD Anderson Cancer Center.
authors.forename: Ravesanker
authors.initials: R
authors.lastname: Ezhilarasan
authors.affiliation: 2Radiation Oncology, The University of Texas MD Anderson Cancer Center.
authors.forename: Patrice
authors.initials: P
authors.lastname: Love
authors.affiliation: 2Radiation Oncology, The University of Texas MD Anderson Cancer Center.
authors.forename: Erik P
authors.initials: EP
authors.lastname: Sulman
authors.affiliation: Departments of1Neurosurgery and.
authors.forename: Frederick F
authors.initials: FF
authors.lastname: Lang
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000473:pathology / Q000503:physiopathology / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000528:radiation effects; D018932:Chemokine CCL2 / Q000378:metabolism; D004307:Dose-Response Relationship, Radiation; D005910:Glioma / Q000473:pathology / Q000503:physiopathology / Q000532:radiotherapy*; D006801:Humans; D008297:Male; D059630:Mesenchymal Stem Cells / Q000473:pathology / Q000502:physiology / Q000528:radiation effects*; D008819:Mice, Nude; D011839:Radiation, Ionizing; D018523:Tropism / Q000528:radiation effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: D018932:Chemokine CCL2
keywords: BBB = blood-brain barrier; CCL2; CM = conditioned medium; DMSO = dimethyl sulfoxide; EGF = epidermal growth factor; GBM = glioblastoma; GFP = green fluorescent protein; GSC = glioma stem-like cell; IR = ionizing radiation; MCP-1; MSC = mesenchymal stem cell; PBS = phosphate-buffered saline; PDGF = platelet-derived growth factor; TGF-β1 = transforming growth factor–β1; dH2O = deionized water; glioma; hMSC = human MSC; mesenchymal stem cells; oncology; radiation; α-MEM = α-minimum essential medium