TNFα secreted by glioma associated macrophages promotes endothelial activation and resistance against anti-angiogenic therapy
Abstract One of the most prominent features of glioblastoma (GBM) is hyper-vascularization. Bone marrow-derived macrophages are actively recruited to the tumor and referred to as glioma-associated macrophages (GAMs) which are thought to provide a critical role in tumor neo-vascularization. However,...
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| Format: | Article |
| Language: | English |
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BMC
2021-04-01
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| Series: | Acta Neuropathologica Communications |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s40478-021-01163-0 |
| _version_ | 1818965437655810048 |
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| author | Qingxia Wei Olivia Singh Can Ekinci Jaspreet Gill Mira Li Yasin Mamatjan Shirin Karimi Severa Bunda Sheila Mansouri Kenneth Aldape Gelareh Zadeh |
| author_facet | Qingxia Wei Olivia Singh Can Ekinci Jaspreet Gill Mira Li Yasin Mamatjan Shirin Karimi Severa Bunda Sheila Mansouri Kenneth Aldape Gelareh Zadeh |
| author_sort | Qingxia Wei |
| collection | DOAJ |
| description | Abstract One of the most prominent features of glioblastoma (GBM) is hyper-vascularization. Bone marrow-derived macrophages are actively recruited to the tumor and referred to as glioma-associated macrophages (GAMs) which are thought to provide a critical role in tumor neo-vascularization. However, the mechanisms by which GAMs regulate endothelial cells (ECs) in the process of tumor vascularization and response to anti-angiogenic therapy (AATx) is not well-understood. Here we show that GBM cells secrete IL-8 and CCL2 which stimulate GAMs to produce TNFα. Subsequently, TNFα induces a distinct gene expression signature of activated ECs including VCAM-1, ICAM-1, CXCL5, and CXCL10. Inhibition of TNFα blocks GAM-induced EC activation both in vitro and in vivo and improve survival in mouse glioma models. Importantly we show that high TNFα expression predicts worse response to Bevacizumab in GBM patients. We further demonstrated in mouse model that treatment with B20.4.1.1, the mouse analog of Bevacizumab, increased macrophage recruitment to the tumor area and correlated with upregulated TNFα expression in GAMs and increased EC activation, which may be responsible for the failure of AATx in GBMs. These results suggest TNFα is a novel therapeutic that may reverse resistance to AATx. Future clinical studies should be aimed at inhibiting TNFα as a concurrent therapy in GBMs. |
| first_indexed | 2024-12-20T13:17:00Z |
| format | Article |
| id | doaj.art-7ecc3b986a5a46198c9763c1e06101bd |
| institution | Directory Open Access Journal |
| issn | 2051-5960 |
| language | English |
| last_indexed | 2024-12-20T13:17:00Z |
| publishDate | 2021-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj.art-7ecc3b986a5a46198c9763c1e06101bd2022-12-21T19:39:30ZengBMCActa Neuropathologica Communications2051-59602021-04-019111910.1186/s40478-021-01163-0TNFα secreted by glioma associated macrophages promotes endothelial activation and resistance against anti-angiogenic therapyQingxia Wei0Olivia Singh1Can Ekinci2Jaspreet Gill3Mira Li4Yasin Mamatjan5Shirin Karimi6Severa Bunda7Sheila Mansouri8Kenneth Aldape9Gelareh Zadeh10MacFeeters Hamilton Centre for Neuro-Oncology Research, Princess Margaret Cancer Centre, University Health NetworkMacFeeters Hamilton Centre for Neuro-Oncology Research, Princess Margaret Cancer Centre, University Health NetworkMacFeeters Hamilton Centre for Neuro-Oncology Research, Princess Margaret Cancer Centre, University Health NetworkMacFeeters Hamilton Centre for Neuro-Oncology Research, Princess Margaret Cancer Centre, University Health NetworkMacFeeters Hamilton Centre for Neuro-Oncology Research, Princess Margaret Cancer Centre, University Health NetworkMacFeeters Hamilton Centre for Neuro-Oncology Research, Princess Margaret Cancer Centre, University Health NetworkMacFeeters Hamilton Centre for Neuro-Oncology Research, Princess Margaret Cancer Centre, University Health NetworkMacFeeters Hamilton Centre for Neuro-Oncology Research, Princess Margaret Cancer Centre, University Health NetworkMacFeeters Hamilton Centre for Neuro-Oncology Research, Princess Margaret Cancer Centre, University Health NetworkMacFeeters Hamilton Centre for Neuro-Oncology Research, Princess Margaret Cancer Centre, University Health NetworkMacFeeters Hamilton Centre for Neuro-Oncology Research, Princess Margaret Cancer Centre, University Health NetworkAbstract One of the most prominent features of glioblastoma (GBM) is hyper-vascularization. Bone marrow-derived macrophages are actively recruited to the tumor and referred to as glioma-associated macrophages (GAMs) which are thought to provide a critical role in tumor neo-vascularization. However, the mechanisms by which GAMs regulate endothelial cells (ECs) in the process of tumor vascularization and response to anti-angiogenic therapy (AATx) is not well-understood. Here we show that GBM cells secrete IL-8 and CCL2 which stimulate GAMs to produce TNFα. Subsequently, TNFα induces a distinct gene expression signature of activated ECs including VCAM-1, ICAM-1, CXCL5, and CXCL10. Inhibition of TNFα blocks GAM-induced EC activation both in vitro and in vivo and improve survival in mouse glioma models. Importantly we show that high TNFα expression predicts worse response to Bevacizumab in GBM patients. We further demonstrated in mouse model that treatment with B20.4.1.1, the mouse analog of Bevacizumab, increased macrophage recruitment to the tumor area and correlated with upregulated TNFα expression in GAMs and increased EC activation, which may be responsible for the failure of AATx in GBMs. These results suggest TNFα is a novel therapeutic that may reverse resistance to AATx. Future clinical studies should be aimed at inhibiting TNFα as a concurrent therapy in GBMs.https://doi.org/10.1186/s40478-021-01163-0GlioblastomaGlioma-associated macrophagesEndothelial cells activationTNFαAnti-angiogenic therapy |
| spellingShingle | Qingxia Wei Olivia Singh Can Ekinci Jaspreet Gill Mira Li Yasin Mamatjan Shirin Karimi Severa Bunda Sheila Mansouri Kenneth Aldape Gelareh Zadeh TNFα secreted by glioma associated macrophages promotes endothelial activation and resistance against anti-angiogenic therapy Acta Neuropathologica Communications Glioblastoma Glioma-associated macrophages Endothelial cells activation TNFα Anti-angiogenic therapy |
| title | TNFα secreted by glioma associated macrophages promotes endothelial activation and resistance against anti-angiogenic therapy |
| title_full | TNFα secreted by glioma associated macrophages promotes endothelial activation and resistance against anti-angiogenic therapy |
| title_fullStr | TNFα secreted by glioma associated macrophages promotes endothelial activation and resistance against anti-angiogenic therapy |
| title_full_unstemmed | TNFα secreted by glioma associated macrophages promotes endothelial activation and resistance against anti-angiogenic therapy |
| title_short | TNFα secreted by glioma associated macrophages promotes endothelial activation and resistance against anti-angiogenic therapy |
| title_sort | tnfα secreted by glioma associated macrophages promotes endothelial activation and resistance against anti angiogenic therapy |
| topic | Glioblastoma Glioma-associated macrophages Endothelial cells activation TNFα Anti-angiogenic therapy |
| url | https://doi.org/10.1186/s40478-021-01163-0 |
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