Hypoxia promotes glioma-associated macrophage infiltration via periostin and subsequent M2 polarization by upregulating TGF-beta and M-CSFR.
Hypoxia promotes glioma-associated macrophage infiltration via periostin and subsequent M2 polarization by upregulating TGF-beta and M-CSFR.
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缺氧通过骨膜素促进神经胶质瘤相关巨噬细胞浸润，并通过上调 TGF-β 和 M-CSFR 促进随后的 M2 极化
DOI：
10.18632/oncotarget.11825
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发表时间：
2016-12-06
期刊：
影响因子：
--
通讯作者：
Li G
中科院分区：
文献类型：
--
作者：
Guo X;Xue H;Shao Q;Wang J;Guo X;Chen X;Zhang J;Xu S;Li T;Zhang P;Gao X;Qiu W;Liu Q;Li G
肿瘤相关巨噬细胞（TAM）在神经胶质瘤中富集，并有助于创造肿瘤免疫抑制微环境。一种独特的M2-偏斜类型的巨噬细胞构成了大多数胶质瘤TAM，并且这些细胞表现出促肿瘤功能。胶质瘤含有大的缺氧区域，并且M2极化TAM的密度与缺氧区域之间的相关性的存在表明缺氧在TAM募集和诱导期间起支持作用。在这里，我们研究了缺氧对人巨噬细胞募集和M2极化的影响。我们还研究了HIF抑制剂acriflavine（ACF）对M2 TAM浸润和体内肿瘤进展的影响。我们发现缺氧增加了胶质瘤细胞中骨膜蛋白（POSTIN）的表达，并促进了巨噬细胞的募集。TGF-α通过RTK/PI 3 K途径增加缺氧诱导的POR 4表达，这种作用可被ACF处理缺氧细胞所阻断。我们还证明了低氧环境和低氧处理的胶质瘤细胞上清液都能够使巨噬细胞向M2表型极化。ACF通过抑制缺氧条件下巨噬细胞M-CSFR和胶质瘤细胞TGF-β的上调，部分逆转了巨噬细胞的M2极化。施用ACF还在体内消融肿瘤进展。我们的研究结果揭示了缺氧诱导的TAM富集和M2极化的基础机制，并表明抑制HIF的HIFs可能会减少M2极化的TAM浸润和胶质瘤进展。
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.