Cancer-Derived Succinate Promotes Macrophage Polarization and Cancer Metastasis via Succinate Receptor

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...

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Published in:Molecular cell Vol. 77; no. 2; p. 213
Main Authors: Wu, Jing-Yiing, Huang, Tsai-Wang, Hsieh, Yi-Ting, Wang, Yi-Fu, Yen, Chia-Chien, Lee, Guan-Lin, Yeh, Chang-Ching, Peng, Yi-Jen, Kuo, Ya-Yi, Wen, Hsiu-Ting, Lin, Hui-Chen, Hsiao, Cheng-Wen, Wu, Kenneth K, Kung, Hsing-Jien, Hsu, Yu-Juei, Kuo, Cheng-Chin
Format: Journal Article
Language:English
Published: United States 16.01.2020
Subjects:
A549 Cells
Animals
Cell Line, Tumor
Cell Movement - physiology
HT29 Cells
Humans
Hypoxia-Inducible Factor 1, alpha Subunit - metabolism
Lung Neoplasms - metabolism
Lung Neoplasms - pathology
Macrophages - metabolism
Macrophages - pathology
MCF-7 Cells
Mice, Inbred C57BL
Neoplasm Metastasis - pathology
PC-3 Cells
Receptors, G-Protein-Coupled - metabolism
Signal Transduction - physiology
Succinic Acid - metabolism
Tumor Microenvironment - physiology
succinate
SUCNR1
metabolomics
PI3K-HIF-1α axis
tumor microenvironment
cancer metastasis
tumor-associated macrophages
ISSN:1097-4164, 1097-4164
Online Access:Get more information
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Summary: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.
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ISSN:1097-4164
1097-4164
DOI:10.1016/j.molcel.2019.10.023