Necrotic cells influence migration and invasion of glioblastoma via NF-κB/AP-1-mediated IL-8 regulation

Ahn, S.H.; Park, Hyun-Ju; Ahn, Young Ho; Kim, Sewha; Cho, Min Sun; Kang, Jihee Lee; Choi, Youn Hee

doi:10.1038/srep24552

Cited by 37 publications

(46 citation statements)

References 41 publications

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“…51,105 IL-8 is increased around areas of GB necrosis, driving centrifugal GB cell migration and neutrophil accretions here. 100,103,106 Indeed, higher neutrophil count during standard GB treatment is a poor prognostic sign. 107 Dapsone's ability to cross the blood-brain barrier combined with its inhibitory effect on IL-8 production, neutrophil accretion, and neutrophil homing make it a strong candidate for potential adjunctive GB treatment.…”

Section: Dapsonementioning

confidence: 99%

“…100 Standard radiation of the post-resection GB tumor bed induced an increase in IL-8 expression in radiation-exposed brain tissue, setting the stage for enhanced growth of surviving GB cells 102 given that increasing IL-8 enhances GB growth and motility. 103,104 Heavier IL-8 staining in biopsied human GB tissue is associated with greater microvascular proliferation and shorter overall survival. 105,106 In GB, a subpopulation of cancer stem-like cells (CSCs) exists adjacent to endothelial cells in a perivascular niche.…”

Section: Dapsonementioning

confidence: 99%

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Glioblastoma-synthesized G-CSF and GM-CSF contribute to growth and immunosuppression: Potential therapeutic benefit from dapsone, fenofibrate, and ribavirin

Kast¹,

Hill

Wion

et al. 2017

Tumour Biol.

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Increased ratio of circulating neutrophils to lymphocytes is a common finding in glioblastoma and other cancers. Data reviewed establish that any damage to brain tissue tends to cause an increase in G-CSF and/or GM-CSF (G(M)-CSF) synthesized by the brain. Glioblastoma cells themselves also synthesize G(M)-CSF. G(M)-CSF synthesized by brain due to damage by a growing tumor and by the tumor itself stimulates bone marrow to shift hematopoiesis toward granulocytic lineages away from lymphocytic lineages. This shift is immunosuppressive and generates the relative lymphopenia characteristic of glioblastoma. Any trauma to brain-be it blunt, sharp, ischemic, infectious, cytotoxic, tumor encroachment, or radiation-increases brain synthesis of G(M)-CSF. G(M)-CSF are growth and motility enhancing factors for glioblastomas. High levels of G(M)-CSF contribute to the characteristic neutrophilia and lymphopenia of glioblastoma. Hematopoietic bone marrow becomes entrained with, directed by, and contributes to glioblastoma pathology. The antibiotic dapsone, the lipid-lowering agent fenofibrate, and the antiviral drug ribavirin are Food and Drug Administration-and European Medicines Agency-approved medicines that have potential to lower synthesis or effects of G(M)-CSF and thus deprive a glioblastoma of some of the growth promoting contributions of bone marrow and G(M)-CSF.

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Section: Dapsonementioning

confidence: 99%

Section: Dapsonementioning

confidence: 99%

Glioblastoma-synthesized G-CSF and GM-CSF contribute to growth and immunosuppression: Potential therapeutic benefit from dapsone, fenofibrate, and ribavirin

Kast¹,

Hill

Wion

et al. 2017

Tumour Biol.

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“…Previous studies have also indicated that the Wnt signaling pathway serves an important role in mediating cell-cell adhesion and beta-catenin self-phosphorylation in tumor cells (70,71). Therefore, the PI3K/AKT, NF-κB and Wnt signaling pathways are closely associated with IL-8 and EMT (62,72). The signaling pathways and factors associated with EMT in tumor cell proliferation, metastasis, invasion and angiogenesis are displayed in Table I (11,12,14,(73)(74)(75)(76)(77)(78)(79)(80)(81)(82)(83).…”

Section: Signaling Pathways Associated With Il-8mentioning

confidence: 99%

“…Furthermore, a previous study has demonstrated that the blockade of CXCR1 with a CXCR1-specific blocking antibody or repertaxin, the small-molecule inhibitor of IL-8, was able to inhibit angiogenesis, invasion, metastasis and tumor progression in xenograft tumor models (97,98). IL-8 is able to promote cell migration, invasion, and metastasis (72). IL-8 also serves a vital role in EMT and can regulate the tumor microenvironment (6).…”

Section: Effects Of Il-8 On Emt In the Tumor Microenvironmentmentioning

confidence: 99%

Epithelial-mesenchymal transition in cancer: Role of the IL-8/IL-8R axis

et al. 2017

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Abstract. Epithelial-mesenchymal transition (EMT) is a biological process that is associated with cancer metastasis and invasion. In cancer, EMT promotes cell motility, invasion and distant metastasis. Interleukin (IL)-8 is highly expressed in tumors and may induce EMT. The IL-8/IL-8R axis has a vital role in EMT in carcinoma, which is regulated by several signaling pathways, including the transforming growth factor β-spleen associated tyrosine kinase/Src-AKT/extracellular signal-regulated kinase, p38/Jun N-terminal kinase-activating transcription factor-2, phosphoinositide 3-kinase/AKT, nuclear factor-κB and Wnt signaling pathways. Blocking the IL-8/IL-8R signaling pathway may be a novel strategy to reduce metastasis and improve patient survival rates. This review will cover IL-8-IL-8R signaling pathway in tumor epithelial-mesenchymal transition.

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“…EMSA was performed with 3 μg of nuclear extracts, as previously described [6]. Briefly, nuclear extracts from CRT-MG treated with or without necrotic cells were incubated with the CCL2/MCP-1 or CCL20/MIP-3α sequences including putative NF-κB or AP-1 binding element, which was end-labeled with [ 32 P] ATP using T4 polynucleotide kinase (New England Biolabs, Inc (NEB), Ipswich, MA, USA).…”

Section: Electrophoretic Mobility Shift Assays (Emsa)mentioning

confidence: 99%

MCP-1 and MIP-3α Secreted from Necrotic Cell-Treated Glioblastoma Cells Promote Migration/Infiltration of Microglia

Jung

Ahn

Park

et al. 2018

Cell Physiol Biochem

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Background/Aims: Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults. The defining characteristics of GBM are diffuse infiltration of tumor cells into normal brain parenchyma, rapid growth, a high degree of infiltration of microglia and macrophages, and the presence of necrosis. Microglia/macrophages are frequently found in gliomas and they extensively infiltrate GBM tissue, up to 30% of total tumor mass. However, little is known about the effect of necrotic cells (NCs) on microglia infiltration in GBM and the tumor-infiltrating microglia-induced factors in GBMs. Methods: In this study, to address whether necrosis or necrosis-exposed GBM cells affect the degree of microglia/macrophage infiltration, migration and invasion/infiltration assays were performed. Culture supernatants and nuclear extracts of CRT-MG cells treated or untreated with necrotic cells were analyzed using a chemokine array and electrophoretic mobility shift assay, respectively. Results: The presence of NCs promoted the migration/infiltration of microglia, and GBM cell line CRT-MG cells exposed to NCs further enhanced the migration and infiltration of HMO6 microglial cells. Treatment with NCs induced mRNA and protein expression of chemokines such as Monocyte Chemoattractant Protein-1 (CCL2/MCP-1) and Macrophage Inflammatory Protein-3α (CCL20/MIP-3α) in CRT-MG cells. In particular, CCL2/MCP-1 and CCL20/MIP-3α were significantly increased in NC-treated CRT-MG cells. NCs induced DNA binding of the transcription factors Nuclear Factor (NF)-κB and Activator Protein 1 (AP-1) to the CCL2/MCP-1 and CCL20/MIP-3α promoters, leading to increased CCL2/MCP-1 and CCL20/MIP-3α mRNA and protein expression in CRT-MG cells. Conclusion: These results provide evidence that NCs induce the expression of CCL2/MCP-1 and CCL20/MIP-3α in glioblastoma cells through activation of NF-κB and AP-1 and facilitate the infiltration of microglia into tumor tissues.

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Necrotic cells influence migration and invasion of glioblastoma via NF-κB/AP-1-mediated IL-8 regulation

Cited by 37 publications

References 41 publications

Glioblastoma-synthesized G-CSF and GM-CSF contribute to growth and immunosuppression: Potential therapeutic benefit from dapsone, fenofibrate, and ribavirin

Glioblastoma-synthesized G-CSF and GM-CSF contribute to growth and immunosuppression: Potential therapeutic benefit from dapsone, fenofibrate, and ribavirin

Epithelial-mesenchymal transition in cancer: Role of the IL-8/IL-8R axis

MCP-1 and MIP-3α Secreted from Necrotic Cell-Treated Glioblastoma Cells Promote Migration/Infiltration of Microglia

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