RESUMO
The invasiveness of malignant gliomas is one of the major obstacles in glioma therapy and the reason for the poor survival of patients. Glioma cells infiltrate into the brain parenchyma and thereby escape surgical resection. Glioma associated microglia/macrophages support glioma infiltration into the brain parenchyma by increased expression and activation of extracellular matrix degrading proteases such as matrix metalloprotease (MMP) 2, MMP9 and membrane-type 1 MMP. In this work we demonstrate that, MMP9 is predominantly expressed by glioma associated microglia/macrophages in mouse and human glioma tissue but not by the glioma cells. Supernatant from glioma cells induced the expression of MMP9 in cultured microglial cells. Using mice deficient for different Toll-like receptors we identified Toll-like receptor 2/6 as the signaling pathway for the glioma induced upregulation of microglial MMP9. Also in an experimental mouse glioma model, Toll-like receptor 2 deficiency attenuated the upregulation of microglial MMP9. Moreover, glioma supernatant triggered an upregulation of Toll-like receptor 2 expression in microglia. Both, the upregulation of MMP9 and Toll-like receptor 2 were attenuated by the antibiotic minocycline and a p38 mitogen-activated protein kinase antagonist in vitro. Minocycline also extended the survival rate of glioma bearing mice when given to the drinking water. Thus glioma cells change the phenotype of glioma associated microglia/macrophages in a complex fashion using Toll-like receptor 2 as an important signaling pathway and minocycline further proved to be a potential candidate for adjuvant glioma therapy.
Assuntos
Antibacterianos/farmacologia , Neoplasias Encefálicas/metabolismo , Glioma/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Minociclina/farmacologia , Receptor 2 Toll-Like/metabolismo , Animais , Western Blotting , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Modelos Animais de Doenças , Citometria de Fluxo , Imunofluorescência , Glioma/tratamento farmacológico , Glioma/patologia , Humanos , Técnicas Imunoenzimáticas , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/patologia , Metaloproteinase 9 da Matriz/genética , Camundongos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/efeitos dos fármacos , Receptor 2 Toll-Like/genética , Células Tumorais CultivadasRESUMO
Recent genome-wide studies of malignancies of the central nervous system (CNS) have revolutionized our understanding of the biology of these tumors. This newly gained knowledge provides a wealth of opportunity for biomarker driven clinical research. To date, however, only few of the available molecular markers truly influence clinical decision-making and treatment. The most widely validated markers in neuro-oncology presently are: 1) MGMT promoter methylation as a prognostic and predictive marker in glioblastoma, 2) co-deletion of 1p and 19q differentiating oligodendrogliomas from astrocytomas, 3) IDH1/2 mutations, and 4) select pathway-associated mutations. This article focuses on currently impactful biomarkers in adult and pediatric brain cancers and it provides a perspective on the direction of research in this field.