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Hypoxia promotes glioma-associated macrophage infiltration via periostin and subsequent M2 polarization by upregulating TGF-beta and M-CSFR
Tumor-associated macrophages (TAMs) are enriched in gliomas and help create a tumor-immunosuppressive microenvironment. A distinct M2-skewed type of macrophages makes up the majority of glioma TAMs, and these cells exhibit pro-tumor functions. Gliomas contain large hypoxic areas, and the presence of...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5348338/ https://www.ncbi.nlm.nih.gov/pubmed/27602954 http://dx.doi.org/10.18632/oncotarget.11825 |
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author | Guo, Xiaofan Xue, Hao Shao, Qianqian Wang, Jian Guo, Xing Chen, Xi Zhang, Jinsen Xu, Shugang Li, Tong Zhang, Ping Gao, Xiao Qiu, Wei Liu, Qinglin Li, Gang |
author_facet | Guo, Xiaofan Xue, Hao Shao, Qianqian Wang, Jian Guo, Xing Chen, Xi Zhang, Jinsen Xu, Shugang Li, Tong Zhang, Ping Gao, Xiao Qiu, Wei Liu, Qinglin Li, Gang |
author_sort | Guo, Xiaofan |
collection | PubMed |
description | Tumor-associated macrophages (TAMs) are enriched in gliomas and help create a tumor-immunosuppressive microenvironment. A distinct M2-skewed type of macrophages makes up the majority of glioma TAMs, and these cells exhibit pro-tumor functions. Gliomas contain large hypoxic areas, and the presence of a correlation between the density of M2-polarized TAMs and hypoxic areas suggests that hypoxia plays a supportive role during TAM recruitment and induction. Here, we investigated the effects of hypoxia on human macrophage recruitment and M2 polarization. We also investigated the influence of the HIF inhibitor acriflavine (ACF) on M2 TAM infiltration and tumor progression in vivo. We found that hypoxia increased periostin (POSTN) expression in glioma cells and promoted the recruitment of macrophages. Hypoxia-inducible POSTN expression was increased by TGF-α via the RTK/PI3K pathway, and this effect was blocked by treating hypoxic cells with ACF. We also demonstrated that both a hypoxic environment and hypoxia-treated glioma cell supernatants were capable of polarizing macrophages toward a M2 phenotype. ACF partially reversed the M2 polarization of macrophages by inhibiting the upregulation of M-CSFR in macrophages and TGF-β in glioma cells under hypoxic conditions. Administering ACF also ablated tumor progression in vivo. Our findings reveal a mechanism that underlies hypoxia-induced TAM enrichment and M2 polarization and suggest that pharmacologically inhibiting HIFs may reduce M2-polarized TAM infiltration and glioma progression. |
format | Online Article Text |
id | pubmed-5348338 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-53483382017-03-31 Hypoxia promotes glioma-associated macrophage infiltration via periostin and subsequent M2 polarization by upregulating TGF-beta and M-CSFR Guo, Xiaofan Xue, Hao Shao, Qianqian Wang, Jian Guo, Xing Chen, Xi Zhang, Jinsen Xu, Shugang Li, Tong Zhang, Ping Gao, Xiao Qiu, Wei Liu, Qinglin Li, Gang Oncotarget Research Paper Tumor-associated macrophages (TAMs) are enriched in gliomas and help create a tumor-immunosuppressive microenvironment. A distinct M2-skewed type of macrophages makes up the majority of glioma TAMs, and these cells exhibit pro-tumor functions. Gliomas contain large hypoxic areas, and the presence of a correlation between the density of M2-polarized TAMs and hypoxic areas suggests that hypoxia plays a supportive role during TAM recruitment and induction. Here, we investigated the effects of hypoxia on human macrophage recruitment and M2 polarization. We also investigated the influence of the HIF inhibitor acriflavine (ACF) on M2 TAM infiltration and tumor progression in vivo. We found that hypoxia increased periostin (POSTN) expression in glioma cells and promoted the recruitment of macrophages. Hypoxia-inducible POSTN expression was increased by TGF-α via the RTK/PI3K pathway, and this effect was blocked by treating hypoxic cells with ACF. We also demonstrated that both a hypoxic environment and hypoxia-treated glioma cell supernatants were capable of polarizing macrophages toward a M2 phenotype. ACF partially reversed the M2 polarization of macrophages by inhibiting the upregulation of M-CSFR in macrophages and TGF-β in glioma cells under hypoxic conditions. Administering ACF also ablated tumor progression in vivo. Our findings reveal a mechanism that underlies hypoxia-induced TAM enrichment and M2 polarization and suggest that pharmacologically inhibiting HIFs may reduce M2-polarized TAM infiltration and glioma progression. Impact Journals LLC 2016-09-02 /pmc/articles/PMC5348338/ /pubmed/27602954 http://dx.doi.org/10.18632/oncotarget.11825 Text en Copyright: © 2016 Guo et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Guo, Xiaofan Xue, Hao Shao, Qianqian Wang, Jian Guo, Xing Chen, Xi Zhang, Jinsen Xu, Shugang Li, Tong Zhang, Ping Gao, Xiao Qiu, Wei Liu, Qinglin Li, Gang Hypoxia promotes glioma-associated macrophage infiltration via periostin and subsequent M2 polarization by upregulating TGF-beta and M-CSFR |
title | Hypoxia promotes glioma-associated macrophage infiltration via periostin and subsequent M2 polarization by upregulating TGF-beta and M-CSFR |
title_full | Hypoxia promotes glioma-associated macrophage infiltration via periostin and subsequent M2 polarization by upregulating TGF-beta and M-CSFR |
title_fullStr | Hypoxia promotes glioma-associated macrophage infiltration via periostin and subsequent M2 polarization by upregulating TGF-beta and M-CSFR |
title_full_unstemmed | Hypoxia promotes glioma-associated macrophage infiltration via periostin and subsequent M2 polarization by upregulating TGF-beta and M-CSFR |
title_short | Hypoxia promotes glioma-associated macrophage infiltration via periostin and subsequent M2 polarization by upregulating TGF-beta and M-CSFR |
title_sort | hypoxia promotes glioma-associated macrophage infiltration via periostin and subsequent m2 polarization by upregulating tgf-beta and m-csfr |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5348338/ https://www.ncbi.nlm.nih.gov/pubmed/27602954 http://dx.doi.org/10.18632/oncotarget.11825 |
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