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 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.
Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, Shandong Province, P.R. China.|Brain Science Research Institute, Shandong University, Jinan, Shandong Province, P.R. China.
Xiaofan
X
Guo
Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, Shandong Province, P.R. China.|Brain Science Research Institute, Shandong University, Jinan, Shandong Province, P.R. China.
Hao
H
Xue
Institute of Basic Medical Sciences and Key Laboratory of Cardiovascular Proteomics of Shandong Province, P.R. China.
Qianqian
Q
Shao
Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, Shandong Province, P.R. China.|Brain Science Research Institute, Shandong University, Jinan, Shandong Province, P.R. China.|Department of Biomedicine, University of Bergen, Bergen, Norway.
Jian
J
Wang
Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, Shandong Province, P.R. China.|Brain Science Research Institute, Shandong University, Jinan, Shandong Province, P.R. China.
Xing
X
Guo
Institute of Basic Medical Sciences and Key Laboratory of Cardiovascular Proteomics of Shandong Province, P.R. China.
Xi
X
Chen
Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, Shandong Province, P.R. China.|Brain Science Research Institute, Shandong University, Jinan, Shandong Province, P.R. China.
Jinsen
J
Zhang
Department of Neurosurgery, Dezhou People's Hospital, Dezhou, Shandong Province, P.R. China.
Shugang
S
Xu
Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, Shandong Province, P.R. China.|Brain Science Research Institute, Shandong University, Jinan, Shandong Province, P.R. China.
Tong
T
Li
Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, Shandong Province, P.R. China.|Brain Science Research Institute, Shandong University, Jinan, Shandong Province, P.R. China.
Ping
P
Zhang
Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, Shandong Province, P.R. China.|Brain Science Research Institute, Shandong University, Jinan, Shandong Province, P.R. China.
Xiao
X
Gao
Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, Shandong Province, P.R. China.|Brain Science Research Institute, Shandong University, Jinan, Shandong Province, P.R. China.
Wei
W
Qiu
Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, Shandong Province, P.R. China.|Brain Science Research Institute, Shandong University, Jinan, Shandong Province, P.R. China.
Qinglin
Q
Liu
Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, Shandong Province, P.R. China.|Brain Science Research Institute, Shandong University, Jinan, Shandong Province, P.R. China.
Gang
G
Li
D000167:Acriflavine / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D002450:Cell Communication; D000066670:Cell Plasticity; D049109:Cell Proliferation; D002633:Chemotaxis; D016207:Cytokines / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D005910:Glioma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D034622:RNA Interference; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D015398:Signal Transduction; D000074084:THP-1 Cells; D013997:Time Factors; D014162:Transfection; D016211:Transforming Growth Factor alpha / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D047368:Tumor Burden; D000072258:Tumor Hypoxia; D059016:Tumor Microenvironment; D015854:Up-Regulation; D016186:Receptor, Macrophage Colony-Stimulating Factor
D000167:Acriflavine; D000970:Antineoplastic Agents; D015815:Cell Adhesion Molecules; D016207:Cytokines; D066246:ErbB Receptors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D058539:Phosphatidylinositol 3-Kinase; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D016211:Transforming Growth Factor alpha; D016212:Transforming Growth Factor beta; C000622186:CSF1R protein, human; D016186:Receptor, Macrophage Colony-Stimulating Factor; C497442:HIF1A protein, human; C512835:POSTN protein, human; C512478:EGFR protein, human
M2 macrophage; acriflavine; glioma; hypoxia; tumor-associated macrophage