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. Dr. Cheng-Chin Kuo and his team from the Institute of Cellular and System Medicine used comparative metabolomics coupled with biochemical and animal studies to demonstrate that cancer cells release succinate into their microenvironment and activate succinate receptor (SUCNR1) signaling to polarize macrophages into TAM.
In addition, 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. Dr. Kuo’s findings indicate that the secreted tumor-derived succinate belongs to a novel class of cancer progression factors, controlling TAM polarization and promoting tumorigenic signaling, and may be a valuable target for cancer chemoprevention and therapy.
Citations: Wu, JY; Huang, TW; Hsieh, YT; Wang, YF; Yen, CC; Lee, GL;Y eh, CC; Peng, YJ; Kuo, YY; Wen, HT; Lin, HC; Hsiao, CW; Wu, KK; Kung, HJ; Hsu, YJ; Kuo, CC. Cancer-derived succinate promotes macrophage polarization and cancer metastasis via succinate receptor. Molecular Cell. 2020 Jan;77(2):213-227.e5