Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan.
Division of Thoracic Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
Mol Cell. 2020 Jan 16;77(2):213-227.e5. doi: 10.1016/j.molcel.2019.10.023. Epub 2019 Nov 14.
Macrophages form a major cell population in the tumor microenvironment. They can be activated and polarized into tumor-associated macrophages (TAM) by the tumor-derived soluble molecules to promote tumor progression and metastasis. Here, we used comparative metabolomics coupled with biochemical and animal studies to show that cancer cells release succinate into their microenvironment and activate succinate receptor (SUCNR1) signaling to polarize macrophages into TAM. Furthermore, the results from in vitro and in vivo studies revealed that succinate promotes not only cancer cell migration and invasion but also cancer metastasis. These effects are mediated by SUCNR1-triggered PI3K-hypoxia-inducible factor 1α (HIF-1α) axis. Compared with healthy subjects and tumor-free lung tissues, serum succinate levels and lung cancer SUCNR1 expression were elevated in lung cancer patients, suggesting an important clinical relevance. Collectively, our findings indicate that the secreted tumor-derived succinate belongs to a novel class of cancer progression factors, controlling TAM polarization and promoting tumorigenic signaling.
巨噬细胞是肿瘤微环境中的主要细胞群体。肿瘤来源的可溶性分子可将其激活并极化成为肿瘤相关巨噬细胞（TAM），从而促进肿瘤的进展和转移。在这里，我们使用比较代谢组学结合生化和动物研究表明，癌细胞将琥珀酸释放到其微环境中，并激活琥珀酸受体（SUCNR1）信号，将巨噬细胞极化为 TAM。此外，体外和体内研究的结果表明，琥珀酸不仅促进了癌细胞的迁移和侵袭，还促进了癌症转移。这些作用是由 SUCNR1 触发的 PI3K-缺氧诱导因子 1α（HIF-1α）轴介导的。与健康受试者和无肿瘤肺组织相比，肺癌患者的血清琥珀酸水平和肺癌 SUCNR1 表达升高，提示其具有重要的临床相关性。总的来说，我们的研究结果表明，肿瘤来源的分泌性琥珀酸属于一类新型的癌症进展因子，控制 TAM 极化并促进致癌信号。
