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

Nature. 2014 Sep 25;513(7519):559-63. doi: 10.1038/nature13490. Epub 2014 Jul 13.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arginase / genetics
  • Arginase / metabolism
  • Carcinoma, Lewis Lung / pathology
  • Cell Communication / drug effects
  • Cell Division / drug effects
  • Culture Media, Conditioned / chemistry
  • Culture Media, Conditioned / pharmacology
  • Female
  • Glycolysis
  • Homeostasis
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Lactic Acid / metabolism*
  • Lactic Acid / pharmacology
  • Macrophages / metabolism*
  • Macrophages / pathology*
  • Male
  • Melanoma, Experimental / pathology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Neoplasms / metabolism*
  • Neoplasms / pathology*
  • RNA, Messenger / analysis
  • RNA, Messenger / genetics
  • Solubility
  • Up-Regulation / drug effects
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / metabolism

Substances

  • Culture Media, Conditioned
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • RNA, Messenger
  • Vascular Endothelial Growth Factor A
  • Lactic Acid
  • Arginase