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      TNFα secreted by glioma associated macrophages promotes endothelial activation and resistance against anti-angiogenic therapy

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          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.

          Supplementary Information

          The online version contains supplementary material available at 10.1186/s40478-021-01163-0.

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          Most cited references43

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          Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma

          Glioblastoma, the most common primary brain tumor in adults, is usually rapidly fatal. The current standard of care for newly diagnosed glioblastoma is surgical resection to the extent feasible, followed by adjuvant radiotherapy. In this trial we compared radiotherapy alone with radiotherapy plus temozolomide, given concomitantly with and after radiotherapy, in terms of efficacy and safety. Patients with newly diagnosed, histologically confirmed glioblastoma were randomly assigned to receive radiotherapy alone (fractionated focal irradiation in daily fractions of 2 Gy given 5 days per week for 6 weeks, for a total of 60 Gy) or radiotherapy plus continuous daily temozolomide (75 mg per square meter of body-surface area per day, 7 days per week from the first to the last day of radiotherapy), followed by six cycles of adjuvant temozolomide (150 to 200 mg per square meter for 5 days during each 28-day cycle). The primary end point was overall survival. A total of 573 patients from 85 centers underwent randomization. The median age was 56 years, and 84 percent of patients had undergone debulking surgery. At a median follow-up of 28 months, the median survival was 14.6 months with radiotherapy plus temozolomide and 12.1 months with radiotherapy alone. The unadjusted hazard ratio for death in the radiotherapy-plus-temozolomide group was 0.63 (95 percent confidence interval, 0.52 to 0.75; P<0.001 by the log-rank test). The two-year survival rate was 26.5 percent with radiotherapy plus temozolomide and 10.4 percent with radiotherapy alone. Concomitant treatment with radiotherapy plus temozolomide resulted in grade 3 or 4 hematologic toxic effects in 7 percent of patients. The addition of temozolomide to radiotherapy for newly diagnosed glioblastoma resulted in a clinically meaningful and statistically significant survival benefit with minimal additional toxicity. Copyright 2005 Massachusetts Medical Society.
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            Microenvironmental regulation of tumour angiogenesis

            This Review discusses the extrinsic regulation of angiogenesis by the tumour microenvironment, highlighting potential vulnerabilities that could be targeted to improve the applicability and reach of anti-angiogenic cancer therapies.
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              Chemokines: a new classification system and their role in immunity.

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                Author and article information

                Contributors
                Qingxia.wei@uhnresearch.ca
                Olivia.Singh@uhnresearch.ca
                cekinci@ku.edu.tr
                jaspreet_gill10@hotmail.com
                Mira.Li@uhnresearch.ca
                Yasheng.Maimaitijiang@uhnresearch.ca
                shirinkarimi2012@gmail.com
                Severa.Bunda@uhnresearch.ca
                mansourisheila@gmail.com
                kenneth.aldape@nih.gov
                gelareh.zadeh@uhn.ca
                Journal
                Acta Neuropathol Commun
                Acta Neuropathol Commun
                Acta Neuropathologica Communications
                BioMed Central (London )
                2051-5960
                14 April 2021
                14 April 2021
                2021
                : 9
                : 67
                Affiliations
                [1 ]GRID grid.231844.8, ISNI 0000 0004 0474 0428, MacFeeters Hamilton Centre for Neuro-Oncology Research, Princess Margaret Cancer Centre, , University Health Network, ; Toronto, ON M5G 1L7 Canada
                [2 ]GRID grid.417188.3, ISNI 0000 0001 0012 4167, University Health Network, Toronto Western Hospital, ; Toronto, Canada
                [3 ]GRID grid.17063.33, ISNI 0000 0001 2157 2938, Division of Neurosurgery, Department of Surgery, , The University of Toronto, ; 399 Bathurst Street, West Wing 4-439, Toronto, ON M5T 2S8 Canada
                Article
                1163
                10.1186/s40478-021-01163-0
                8048292
                33853689
                47556d3c-5ab3-4506-b71f-00cf93318150
                © The Author(s) 2021

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                : 6 January 2021
                : 19 March 2021
                Funding
                Funded by: CIHR
                Award ID: CIHR# 159452
                Award Recipient :
                Funded by: Wilkins Family Foundation
                Categories
                Research
                Custom metadata
                © The Author(s) 2021

                glioblastoma,glioma-associated macrophages,endothelial cells activation,tnfα,anti-angiogenic therapy

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