School of Life Sciences, BK21 FOUR KNU Creative BioResearch Group, Kyungpook National University, Daegu, 41566, Republic of Korea.
School of Life Sciences & Biotechnology, College of Natural Sciences, Kyungpook National University, Daegu, 41566, Republic of Korea.
Mol Med. 2024 Sep 10;30(1):143. doi: 10.1186/s10020-024-00911-x.
Targeting the tumor microenvironment represents an emerging therapeutic strategy for cancer. Macrophages are an essential part of the tumor microenvironment. Macrophage polarization is modulated by mitochondrial metabolism, including oxidative phosphorylation (OXPHOS), the tricarboxylic acid (TCA) cycle, and reactive oxygen species content. Isocitrate dehydrogenase 2 (IDH2), an enzyme involved in the TCA cycle, reportedly promotes cancer progression. However, the mechanisms through which IDH2 influences macrophage polarization and modulates tumor growth remain unknown.
In this study, IDH2-deficient knockout (KO) mice and primary cultured bone marrow-derived macrophages (BMDMs) were used. Both in vivo subcutaneous tumor experiments and in vitro co-culture experiments were performed, and samples were collected for analysis. Western blotting, RNA quantitative analysis, immunohistochemistry, and flow cytometry were employed to confirm changes in mitochondrial function and the resulting polarization of macrophages exposed to the tumor microenvironment. To analyze the effect on tumor cells, subcutaneous tumor size was measured, and growth and metastasis markers were identified.
IDH2-deficient macrophages co-cultured with cancer cells were found to possess increased mitochondrial dysfunction and fission than wild-type BMDM. Additionally, the levels of M2-associated markers decreased, whereas M1-associated factor levels increased in IDH2-deficient macrophages. IDH2-deficient macrophages were predominantly M1. Tumor sizes in the IDH2-deficient mouse group were significantly smaller than in the wild-type mouse group. IDH2 deficiency in macrophages was associated with inhibited tumor growth and epithelial-mesenchymal transition.
Our findings suggest that IDH2 deficiency inhibits M2 macrophage polarization and suppresses tumorigenesis. This study underlines the potential contribution of IDH2 expression in macrophages and tumor microenvironment remodeling, which could be useful in clinical cancer research.
靶向肿瘤微环境是癌症治疗的新兴策略。巨噬细胞是肿瘤微环境的重要组成部分。巨噬细胞极化受线粒体代谢调节，包括氧化磷酸化（OXPHOS）、三羧酸（TCA）循环和活性氧含量。参与 TCA 循环的异柠檬酸脱氢酶 2（IDH2）据报道可促进癌症进展。然而，IDH2 影响巨噬细胞极化和调节肿瘤生长的机制尚不清楚。
本研究使用 IDH2 缺陷型敲除（KO）小鼠和原代培养的骨髓来源巨噬细胞（BMDM）。进行了体内皮下肿瘤实验和体外共培养实验，并收集样本进行分析。采用 Western blot、RNA 定量分析、免疫组织化学和流式细胞术证实暴露于肿瘤微环境后巨噬细胞中线粒体功能的变化及其极化。为分析对肿瘤细胞的影响，测量了皮下肿瘤的大小，并鉴定了生长和转移标志物。
与野生型 BMDM 相比，与癌细胞共培养的 IDH2 缺陷型巨噬细胞表现出更高的线粒体功能障碍和裂变。此外，IDH2 缺陷型巨噬细胞中 M2 相关标志物水平降低，而 M1 相关因子水平升高。IDH2 缺陷型巨噬细胞主要为 M1。IDH2 缺陷型小鼠组的肿瘤体积明显小于野生型小鼠组。巨噬细胞中 IDH2 的缺乏与抑制肿瘤生长和上皮-间充质转化有关。
我们的研究结果表明，IDH2 缺陷抑制 M2 巨噬细胞极化并抑制肿瘤发生。本研究强调了 IDH2 在巨噬细胞和肿瘤微环境重塑中的表达潜力，这可能对临床癌症研究有用。
