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Cell Rep. 2017 Aug 15;20(7):1654-1666. doi: 10.1016/j.celrep.2017.07.054.

Pharmacologic or Genetic Targeting of Glutamine Synthetase Skews Macrophages toward an M1-like Phenotype and Inhibits Tumor Metastasis.

Author information

1
Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70125 Bari, Italy; The Cancer and Inflammation Program, National Cancer Institute-Frederick, Frederick, MD 21702, USA.
2
Hematology Unit, National Cancer Research Center, Istituto Tumori "Giovanni Paolo II," 70124 Bari, Italy; Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology (CCB), VIB, 3000 Leuven, Belgium; Laboratory of Tumor Inflammation and Angiogenesis, Department of Oncology, KU Leuven, 3000 Leuven, Belgium.
3
Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology (CCB), VIB, 3000 Leuven, Belgium; Laboratory of Tumor Inflammation and Angiogenesis, Department of Oncology, KU Leuven, 3000 Leuven, Belgium.
4
Hematology Unit, National Cancer Research Center, Istituto Tumori "Giovanni Paolo II," 70124 Bari, Italy.
5
Department of Cancer Biology, Department of Neurological Surgery, Thomas Jefferson University, Philadelphia, PA 19107, USA.
6
Department of Anatomy & Embryology, NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University, 6211 LK Maastricht, the Netherlands; Nutrigenomics Consortium, Top Institute Food and Nutrition, Wageningen, the Netherlands; Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, 1012 WX Amsterdam, the Netherlands.
7
Metabolomics Expertise Center, Vesalius Research Center, VIB, 3000 Leuven, Belgium; Metabolomics Expertise Center, Department of Oncology, KU Leuven, 3000 Leuven, Belgium.
8
The Cancer and Inflammation Program, National Cancer Institute-Frederick, Frederick, MD 21702, USA.
9
Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology (CCB), VIB, 3000 Leuven, Belgium; Laboratory of Tumor Inflammation and Angiogenesis, Department of Oncology, KU Leuven, 3000 Leuven, Belgium. Electronic address: massimiliano.mazzone@vib-kuleuven.be.
10
Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70125 Bari, Italy; Hematology Unit, National Cancer Research Center, Istituto Tumori "Giovanni Paolo II," 70124 Bari, Italy. Electronic address: alessandra.castegna@uniba.it.

Abstract

Glutamine-synthetase (GS), the glutamine-synthesizing enzyme from glutamate, controls important events, including the release of inflammatory mediators, mammalian target of rapamycin (mTOR) activation, and autophagy. However, its role in macrophages remains elusive. We report that pharmacologic inhibition of GS skews M2-polarized macrophages toward the M1-like phenotype, characterized by reduced intracellular glutamine and increased succinate with enhanced glucose flux through glycolysis, which could be partly related to HIF1α activation. As a result of these metabolic changes and HIF1α accumulation, GS-inhibited macrophages display an increased capacity to induce T cell recruitment, reduced T cell suppressive potential, and an impaired ability to foster endothelial cell branching or cancer cell motility. Genetic deletion of macrophagic GS in tumor-bearing mice promotes tumor vessel pruning, vascular normalization, accumulation of cytotoxic T cells, and metastasis inhibition. These data identify GS activity as mediator of the proangiogenic, immunosuppressive, and pro-metastatic function of M2-like macrophages and highlight the possibility of targeting this enzyme in the treatment of cancer metastasis.

KEYWORDS:

HIF1α; IL-10; glutamine; glutamine synthetase; macrophages; metabolic rewiring; metastasis; starvation; succinate

PMID:
28813676
PMCID:
PMC5575233
DOI:
10.1016/j.celrep.2017.07.054
[Indexed for MEDLINE]
Free PMC Article

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