Microglial-stimulation of glioma invasion involves the EGFR ligand amphiregulin
Autor: | Jeffrey E. Segall, Salvatore J. Coniglio |
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Rok vydání: | 2021 |
Předmět: |
MAPK/ERK pathway
Cancer Treatment Biochemistry Mice White Blood Cells RNA interference Animal Cells Breast Tumors Medicine and Health Sciences Neurological Tumors Cultured Tumor Cells Multidisciplinary Microglia Chemistry Brain Neoplasms Glioma Small interfering RNA Up-Regulation ErbB Receptors Gene Expression Regulation Neoplastic Nucleic acids medicine.anatomical_structure Oncology Neurology Medicine Biological Cultures Signal transduction Cellular Types Signal Transduction Research Article Science Immune Cells Immunology Glial Cells Research and Analysis Methods Amphiregulin Malignant Tumors Downregulation and upregulation Cell Line Tumor Breast Cancer medicine Genetics Animals Humans Neoplasm Invasiveness Non-coding RNA Microglial Cells Blood Cells Macrophages Biology and Life Sciences Cancers and Neoplasms Cell Biology Cell Cultures medicine.disease Glioma Cells Gene regulation Mice Inbred C57BL Cell culture Cancer research RNA Gene expression |
Zdroj: | PLoS ONE PLoS ONE, Vol 16, Iss 11, p e0260252 (2021) |
ISSN: | 1932-6203 |
Popis: | High grade glioma is one of the deadliest human cancers with a median survival rate of only one year following diagnosis. The highly motile and invasive nature of high grade glioma makes it difficult to completely remove surgically. Therefore, increasing our knowledge of the mechanisms glioma cells use to invade normal brain is of critical importance in designing novel therapies. It was previously shown by our laboratory that tumor-associated microglia (TAMs) stimulate glioma cell invasion and this process is dependent on CSF-1R signaling. In this study, we seek to identify pro-invasive factors that are upregulated in microglia in a CSF-1R-dependent manner. We assayed cDNA and protein from microglia treated with conditioned media from the murine glioma cell line GL261, and discovered that several EGFR ligands including amphiregulin (AREG) are strongly upregulated. This upregulation is blocked by addition of a pharmacological CSF-1R inhibitor. Using RNA interference, we show that AREG-depleted microglia are less effective at promoting invasion of GL261 cells into Matrigel-coated invasion chambers. In addition, an AREG blocking antibody strongly attenuates the ability of THP-1 macrophages to activate human glioma cell line U87 invasion. Furthermore, we have identified a signaling pathway which involves CSF-1 signaling through ERK to upregulate AREG expression in microglia. Interfering with ERK using pharmacological inhibitors prevents AREG upregulation in microglia and microglia-stimulated GL261 invasion. These data highlight AREG as a key factor in produced by tumor associated microglia in promoting glioma invasion. |
Databáze: | OpenAIRE |
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