1. Glioma sensitive or chemoresistant to temozolomide differentially modulate macrophage protumor activities.
- Author
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Azambuja JH, da Silveira EF, de Carvalho TR, Oliveira PS, Pacheco S, do Couto CT, Beira FT, Stefanello FM, Spanevello RM, and Braganhol E
- Subjects
- Animals, Antineoplastic Agents, Alkylating administration & dosage, Antioxidants metabolism, Apoptosis drug effects, Cell Line, Tumor, Cell Polarity drug effects, Dacarbazine administration & dosage, Disease Models, Animal, Glioma metabolism, Glioma pathology, Humans, Inflammation metabolism, Inflammation pathology, Macrophages drug effects, Macrophages metabolism, Mice, Receptors, Purinergic genetics, Temozolomide, Tumor Microenvironment drug effects, Dacarbazine analogs & derivatives, Drug Resistance, Neoplasm genetics, Glioma drug therapy, Inflammation drug therapy
- Abstract
Background: Glioblastomas are the most devastating brain tumor characterized by chemoresistance development and poor prognosis. Macrophages are a component of tumor microenvironment related to glioma malignancy. The relation among inflammation, innate immunity and cancer is accepted; however, molecular and cellular mechanisms mediating this relation and chemoresistance remain unresolved., Objective: Here we evaluated whether glioma sensitive or resistant to temozolomide (TMZ) modulate macrophage polarization and inflammatory pathways associated. The impact of glioma-macrophage crosstalk on glioma proliferation was also investigated., Methods: GL261 glioma chemoresistance was developed by exposing cells to increasing TMZ concentrations over a period of 6months. Mouse peritoneal macrophages were exposed to glioma-conditioned medium or co-cultured directly with glioma sensitive (GL) or chemoresistant (GLTMZ). Macrophage polarization, in vitro and in vivo glioma proliferation, redox parameters, ectonucleotidase activity and ATP cytotoxicity were performed., Results: GLTMZ cells were more effective than GL in induce M2-like macrophage polarization and in promote a strong immunosuppressive environment characterized by high IL-10 release and increased antioxidant potential, which may contribute to glioma chemoresistance and proliferation. Interestingly, macrophage-GLTMZ crosstalk enhanced in vitro and in vivo proliferation of chemoresistant cells, decreased ectonucleotidase activities, which was followed by increased macrophage sensitivity to ATP induced death., Conclusions: Results suggest a differential macrophage modulation by GLTMZ cells, which may favor the maintenance of immunosuppressive tumor microenvironment and glioma proliferation., General Significance: The induction of immunosuppressive environment and macrophage education by chemoresistant gliomas may be important for tumor recovery after chemotherapy and could be considered to overcome chemoresistance development., (Copyright © 2017. Published by Elsevier B.V.)
- Published
- 2017
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