Malignant gliomas are characterized by a short median survival which is largely impacted by the resistance of these tumors to chemo-and radiotherapy. Recent studies suggest that a small subpopulation of cancer stem cells, which are highly resistant to cradiation, has the capacity to repopulate the tumors and contribute to their malignant progression. c-radiation activates the process of autophagy and inhibition of this process increases the radiosensitivity of glioma cells; however, the role of autophagy in the resistance of glioma stem cells (GSCs) to radiation has not been yet reported. In this study we examined the induction of autophagy by c-radiation in CD1331 GSCs. Irradiation of CD1331 cells induced autophagy within 24-48 hr and slightly decreased the viability of the cells. c-radiation induced a larger degree of autophagy in the CD1331 cells as compared with CD1332 cells and the CD1331 cells expressed higher levels of the autophagy-related proteins LC3, ATG5 and ATG12. The autophagy inhibitor bafilomycin A1 and silencing of ATG5 and beclin1 sensitized the CD1331 cells to c-radiation and significantly decreased the viability of the irradiated cells and their ability to form neurospheres. Collectively, these results indicate that the induction of autophagy contributes to the radioresistance of these cells and autophagy inhibitors may be employed to increase the sensitivity of CD1331 GSCs to c-radiation. ' UICCKey words: autophagy; glioma stem cells; c-radiation; ATG5; ATG12 Glioblastomas (GBMs), the most frequent and aggressive primary brain tumors, are characterized by increased proliferation, resistance to chemotherapy and radiotherapy and invasion into the surrounding normal brain tissue. 1,2 Current treatments include surgery, radiation therapy and chemotherapy. 3,4 Unfortunately, the prognosis of patients with GBMs remains extremely poor and has not changed significantly during the past several years. 5,6 Therefore, novel therapeutic approaches are needed to improve the poor prognosis of these patients.Recently, a small subpopulation of CD1331 cancer stem cells has been identified in specimens of GBM. 7,8 These glioma stem cells (GSCs) express additional stem cell markers, exhibit selfrenewal and differentiation to glial and neuronal lineages, and can initiate xenograft tumors. 9,10 Cancer stem cells in various tumors, including the GSCs, have been implicated in the enhanced radioresistance and in the repopulation of tumors following these treatments. 10,11 Thus, delineating the molecular mechanisms underlying the increased resistance of these cells to anticancer therapies is of utmost importance.Autophagy is a cellular pathway involved in protein and organelle degradation. 12,13 This process is regulated by a series of autophagy-related genes (ATGs) and a number of signaling molecules such as mTOR, AKT, and class I and class III phosphatidylinositol 3-kinase. 14,15 Autophagy is frequently activated in tumor cells following anticancer therapies such as chemotherapeutic drugs 16,17 or g-irradiation 1...
MicroRNAs (miRNAs) have emerged as potential cancer therapeutics; however, their clinical use is hindered by lack of effective delivery mechanisms to tumor sites. Mesenchymal stem cells (MSCs) have been shown to migrate to experimental glioma and to exert anti-tumor effects by delivering cytotoxic compounds. Here, we examined the ability of MSCs derived from bone marrow, adipose tissue, placenta and umbilical cord to deliver synthetic miRNA mimics to glioma cells and glioma stem cells (GSCs). We examined the delivery of miR-124 and miR-145 mimics as glioma cells and GSCs express very low levels of these miRNAs. Using fluorescently labeled miRNA mimics and in situ hybridization, we demonstrated that all the MSCs examined delivered miR-124 and miR-145 mimics to co-cultured glioma cells and GSCs via gap junction–dependent and independent processes. The delivered miR-124 and miR-145 mimics significantly decreased the luciferase activity of their respected reporter target genes, SCP-1 and Sox2, and decreased the migration of glioma cells and the self-renewal of GSCs. Moreover, MSCs delivered Cy3-miR-124 mimic to glioma xenografts when administered intracranially. These results suggest that MSCs can deliver synthetic exogenous miRNA mimics to glioma cells and GSCs and may provide an efficient route of therapeutic miRNA delivery in vivo.
Glioblastomas (GBM), the most common and aggressive malignant astrocytic tumors, contain a small subpopulation of cancer stem cells (GSCs) that are implicated in therapeutic resistance and tumor recurrence. Here, we study the expression and function of miR-137, a putative suppressor miRNA, in GBM and GSCs. We found that the expression of miR-137 was significantly lower in GBM and GSCs compared to normal brains and neural stem cells (NSCs) and that the miR-137 promoter was hypermethylated in the GBM specimens. The expression of miR-137 was increased in differentiated NSCs and GSCs and overexpression of miR-137 promoted the neural differentiation of both cell types. Moreover, pre-miR-137 significantly decreased the self-renewal of GSCs and the stem cell markers Oct4, Nanog, Sox2 and Shh. We identified RTVP-1 as a novel target of miR-137 in GSCs; transfection of the cells with miR-137 decreased the expression of RTVP-1 and the luciferase activity of RTVP-1 3'-UTR reporter plasmid. Furthermore, overexpression of RTVP-1 plasmid lacking its 3'-UTR abrogated the inhibitory effect of miR-137 on the self-renewal of GSCs. Silencing of RTVP-1 decreased the self-renewal of GSCs and the expression of CXCR4 and overexpression of CXCR4 abrogated the inhibitory effect of RTVP-1 silencing on GSC self-renewal. These results demonstrate that miR-137 is downregulated in GBM probably due to promoter hypermethylation. miR-137 inhibits GSC self-renewal and promotes their differentiation by targeting RTVP-1 which downregulates CXCR4. Thus, miR-137 and RTVP-1 are attractive therapeutic targets for the eradication of GSCs and for the treatment of GBM.
We characterized the expression and function of the endoplasmic reticulum protein GRP78 in glial tumors. GRP78 is highly expressed in glioblastomas but not in oligodendrogliomas, and its expression is inversely correlated with median patient survival. Overexpression of GRP78 in glioma cells decreases caspase 7 activation and renders the cells resistant to etoposide- and cisplatin-induced apoptosis, whereas silencing of GRP78 decreases cell growth and sensitizes glioma cells to etoposide, cisplatin, and gamma-radiation. Thus, GRP78 contributes to the increased apoptosis resistance and growth of glioma cells and may provide a target for enhancing the therapeutic responsiveness of these tumors.
We investigated whether cilengitide could amplify the antitumor effects of radiotherapy in an orthotopic rat glioma xenograft model. Cilengitide is a specific inhibitor of av series integrins, and acts as an antiangiogenic. U251 human glioma cells express avb3 and avb5 integrins. We used in vitro assays of adhesion and growth of tumor and endothelial cells to evaluate cytotoxicity and the potential for cilengitide to enhance radiation toxicity. Treatment was then evaluated in an orthotopic model to evaluate synergy with therapeutic radiation in vivo. In vitro, cilengitide blocked cell adhesion, but did not influence the effects of radiation on U251 cells; cilengitide strongly amplified radiation effects on endothelial cell survival. In vivo, radiotherapy prolonged the survival of U251 tumor-bearing rats from 50 to over 110 days. Cotreatment with cilengitide and radiation dramatically amplified the effects of radiation, producing survival over 200 days and triggering an enhanced apoptotic response and suppression of tumor growth by histology at necropsy. Signaling pathways activated in the tumor included NFjb, a documented mediator of cellular response to radiation. Because cilengitide has a short plasma halflife (t ½ 20 min), antiangiogenic scheduling typically uses daily injections. We found that a single dose of cilengitide (4 mg/kg) given between 4 and 12 hr prior to radiation was sufficient to produce the same effect. Our results demonstrate that blockade of av integrins mediates an unanticipated rapid potentiation of radiation, and suggests possible clinical translation for glioma therapy. ' 2008 Wiley-Liss, Inc.Key words: glioma; cilengitide; integrin; radiation; animal model Integrins control cell attachment to extracellular matrices (ECMs) and participate in cellular defense against genotoxic assaults. 1 These defense mechanisms are a major factor in the resistance of solid malignancies to radiotherapy. In this in vivo study, we examine the effects of an inhibitor of av-integrins, cilengitide, on the growth of gliomas in response to external beam radiotherapy. Malignant gliomas, including anaplastic astrocytoma and glioblastoma multiforme (GBM), are the most common primary brain tumors, afflicting some 6/100,000 individuals annually within the United States. 2 Current treatment options include surgery, radiation therapy (RT) and chemotherapy. But the efficacy of treatment is limited by the infiltrative nature of GBMs, by sustained tumor angiogenesis, and by a marked resistance to chemo and radiotherapies. Indeed, clinical prognosis is poor and the median survival from diagnosis of 12 months in GBM has not changed appreciably over a quarter century. 3 Gliomas, and especially anaplastic gliomas, infiltrate and spread great distances in the brain from a peripheral zone of infiltrating cells in the highly vascularized cellular rim of tumor that surrounds a central necrotic core. 4 The infiltrating tumor cells cause an almost inevitable local recurrence and clinical progression. 5 Recurrence following surger...
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