Hypoxia promotes glioma-associated macrophage infiltration via periostin and subsequent M2 polarization by upregulating TGF-beta and M-CSFR
Abstract
// Xiaofan Guo 1, 2 , Hao Xue 1, 2 , Qianqian Shao 3 , Jian Wang 1, 2, 4 , Xing Guo 1, 2 , Xi Chen 3 , Jinsen Zhang 1, 2 , Shugang Xu 5 , Tong Li 1, 2 , Ping Zhang 1, 2 , Xiao Gao 1, 2 , Wei Qiu 1, 2 , Qinglin Liu 1, 2, * , Gang Li 1, 2, * 1 Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, Shandong Province, P.R. China 2 Brain Science Research Institute, Shandong University, Jinan, Shandong Province, P.R. China 3 Institute of Basic Medical Sciences and Key Laboratory of Cardiovascular Proteomics of Shandong Province, P.R. China 4 Department of Biomedicine, University of Bergen, Bergen, Norway 5 Department of Neurosurgery, Dezhou People’s Hospital, Dezhou, Shandong Province, P.R. China * These authors have contributed equally to this work Correspondence to: Gang Li, email: [email protected] Qinglin Liu, email: [email protected] Keywords: glioma, hypoxia, tumor-associated macrophage, M2 macrophage, acriflavine Received: March 09, 2016 Accepted: August 13, 2016 Published: September 02, 2016 ABSTRACT 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.