Functional polarization of tumour-associated macrophages by tumour-derived lactic acid

By O. Colegio, Ngoc-Quynh Chu, A. Szabo, Thach H Chu, Anne Marie Rhebergen, V. Jairam, N. Cyrus, Carolyn Brokowski, S. Eisenbarth, G. Phillips and 3 more. Nature, 2014

2,705 citations recorded by the source corpus.

Macrophages have an important role in the maintenance of tissue homeostasis. To perform this function, macrophages must have the capacity to monitor the functional states of their ‘client cells’: namely, the parenchymal cells in the various tissues in which macrophages reside. Tumours exhibit many features of abnormally developed organs, including tissue architecture and cellular composition. Similarly to macrophages in normal tissues and organs, macrophages in tumours (tumour-associated macrophages) perform some key homeostatic functions that allow tumour maintenance and growth. However, the signals involved in communication between tumours and macrophages are poorly defined. Here we show that lactic acid produced by tumour cells, as a by-product of aerobic or anaerobic glycolysis, has a critical function in signalling, through inducing the expression of vascular endothelial growth factor and the M2-like polarization of tumour-associated macrophages. Furthermore, we demonstrate that this effect of lactic acid is mediated by hypoxia-inducible factor 1α (HIF1α). Finally, we show that the lactate-induced expression of arginase 1 by macrophages has an important role in tumour growth. Collectively, these findings identify a mechanism of communication between macrophages and their client cells, including tumour cells. This communication most probably evolved to promote homeostasis in normal tissues but can also be engaged in tumours to promote their growth.

Subfields: Cancer Research, Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/dd2a998546d690e0637a80d012edb3f59277b354

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cancer Research

1. S. Shalapour
2. A. Mantovani
3. P. Allavena
4. Erika L. Pearce
5. Michael D. Buck
6. M. Karin
7. Ke Zen
8. S. Kierans

In Immunology

1. A. Mantovani
2. P. Allavena
3. M. Karin
4. S. Shalapour
5. Michael D. Buck
6. Erika L. Pearce
7. S. Kaech
8. R. Sowell

In Molecular Biology

1. M. Karin
2. S. Shalapour
3. P. Allavena
4. Erika L. Pearce
5. A. Mantovani
6. Muyue Yang
7. Xianqun Fan
8. Jipeng Li

Citations in the corpus

• The application of nanoparticles in cancer immunotherapy: Targeting tumor microenvironment (2020, background): “However, a number of molecules found in TME as well as hypoxic environment and lactic acid inhibit the functions of cDCs [29,30].”
• Molecular Mechanisms That Influence the Macrophage M1–M2 Polarization Balance (2014, background): “Moreover, recent studies also showed that HIF-1α can mediate the effects of tumor-derived lactic acid (59) and cytokines (Oncostatin M and Eotaxin) (60) on promoting M2-like phenotype.”
• Progress in tumor-associated macrophage (TAM)-targeted therapeutics (2017, positive): “The TME is enriched for lactate which is secreted by cancer cells performing glycolysis [133].”
• Immunity, inflammation, and cancer: an eternal fight between good and evil. (2015, positive): “At early stages of tumor development, TAMs appear to undergo classical activation and exhibit an M1 phenotype (referred to as TAM1) (61), rather than the alternatively activated M2 phenotype (TAM2), which may form as tumors accumulate lactic acid and acquire hypoxic cores (62).”
• Metabolism via Arginase or Nitric Oxide Synthase: Two Competing Arginine Pathways in Macrophages (2014, background): “This tumor cell-derived lactic acid is a potent inducer of arginase I expression in tumor-associated macrophages (TAM) and these M2/arginase macrophages then foster tumor growth (105).”
• Regulation of glycolysis by the hypoxia‐inducible factor (HIF): implications for cellular physiology (2020, background): “Lactate can also have profound effect on macrophage polarisation, by inducing arginase 1, VEGF and other M2-associated genes in TAMs, thereby resulting in the development of a tumour-promoting phenotype in these cells (Colegio et al. 2014).”
• The P2X7 Receptor in Infection and Inflammation (2017, positive): “In addition, HIF-1a promotes lactic acid-dependent M2 polarization in the tumor microenvironment (Colegio et al., 2014).”
• The Warburg Effect: How Does it Benefit Cancer Cells? (2016, background): “A recent study showed that tumor-derived lactate is a contributor to M2 tissueassociated macrophage (TAM) polarization [44].”
• LDHA-Associated Lactic Acid Production Blunts Tumor Immunosurveillance by T and NK Cells. (2016, background): “showed that lactic acid promotes development of M2-like macrophages by inducing hypoxia-inducible factor 1a (Colegio et al., 2014).”