M2 tumor-associated macrophages resist to oxidative stress through heme oxygenase-1 in the colorectal cancer tumor microenvironment
M2 tumor-associated macrophages resist to oxidative stress through heme oxygenase-1 in the colorectal cancer tumor microenvironment
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DOI：
10.1007/s00262-023-03406-6
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发表时间：
2023-03
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通讯作者：
Misato Ito;Kosaku Mimura;S. Nakajima;H. Okayama;Katsuharu Saito;T. Nakajima;Tomohiro Kikuchi;H. Onozawa;S. Fujita;W. Sakamoto;M. Saito;T. Momma;Z. Saze;Koji Kono
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作者：
Misato Ito;Kosaku Mimura;S. Nakajima;H. Okayama;Katsuharu Saito;T. Nakajima;Tomohiro Kikuchi;H. Onozawa;S. Fujita;W. Sakamoto;M. Saito;T. Momma;Z. Saze;Koji Kono
M2肿瘤相关巨噬细胞(M2-TAMs)促进TME内癌细胞的增殖和转移。本研究旨在通过核因子红系相关因子2(NRF2)途径探讨结直肠癌(CRC)-TME中M2-TAMs侵袭频率增加的机制。在这项研究中，我们使用公共数据集评估M2-信号与抗氧化剂相关基因表达的相关性，并通过流式细胞术评估M2-TAM中抗氧化剂的表达水平，并通过手术切除的结直肠癌标本(n= 34)通过免疫荧光染色评估M2-TAM表达抗氧化剂的发生率。此外，我们从外周血单核细胞中产生了M0和M2巨噬细胞，并通过体外活性试验评估了它们对氧化应激的抵抗力。对GSE33113、GSE39582和肿瘤基因组图谱的分析表明，HMOX1mRNA的表达与M2-信号呈显著正相关(r= 0.5283，r= 0.5826，r= 0.5833)。M2-TAMs中Nrf2和HO-1的表达水平明显高于M1-和M1/M2-TAMs，且肿瘤间质中Nrf2+或HO-1+M2-TAMs的数量显著高于正常黏膜间质。与表达HO-1的M0巨噬细胞相比，表达HO-1的M2巨噬细胞对过氧化氢诱导的氧化应激具有明显的抵抗作用。综上所述，我们的结果提示M2-TAMs在结直肠癌-TME中的渗透频率增加与Nrf2-HO-1轴介导的氧化应激抵抗有关。
M2 tumor-associated macrophages (M2-TAMs) promote cancer cell proliferation and metastasis in the TME. Our study aimed to elucidate the mechanism of increased frequency of M2-TAMs infiltration in the colorectal cancer (CRC)-TME, focusing on the resistance to oxidative stress through nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. In this study, we evaluated the correlation between M2-TAM signature and mRNA expression of antioxidant related genes using public datasets, and the expression level of antioxidants in M2-TAMs by flow cytometry and the prevalence of M2-TAMs expressing antioxidants by immunofluorescence staining using surgically resected specimens of CRC (n= 34). Moreover, we generated M0 and M2 macrophages from peripheral blood monocytes and evaluated their resistance to oxidative stress using the in vitro viability assay. Analysis of GSE33113, GSE39582, and The Cancer Genome Atlas (TCGA) datasets indicated that mRNA expression ofHMOX1(heme oxygenase-1 (HO-1)) was significantly positively correlated with M2-TAM signature (r= 0.5283,r= 0.5826,r= 0.5833, respectively). The expression level of both Nrf2 and HO-1 significantly increased in M2-TAMs compared to M1- and M1/M2-TAMs in the tumor margin, and the number of Nrf2+or HO-1+M2-TAMs in the tumor stroma significantly increased more than those in the normal mucosa stroma. Finally, generated M2 macrophages expressing HO-1 significantly resisted to oxidative stress induced by H2O2in comparison with generated M0 macrophages. Taken together, our results suggested that an increased frequency of M2-TAMs infiltration in the CRC-TME is related to Nrf2–HO-1 axis mediated resistance to oxidative stress.