title: Functional polarization of tumour-associated macrophages by tumour-derived lactic acid.
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.
authors.affiliation: 1] Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06519-1612, USA [2] Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut 06520-8059, USA [3] Yale-New Haven Transplantation Center, Yale University School of Medicine, New Haven, Connecticut 06519-1369, USA [4] Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut 06520-8028, USA.
authors.forename: Oscar R
authors.initials: OR
authors.lastname: Colegio
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06519-1612, USA.
authors.forename: Ngoc-Quynh
authors.initials: NQ
authors.lastname: Chu
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06519-1612, USA.
authors.forename: Alison L
authors.initials: AL
authors.lastname: Szabo
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06519-1612, USA.
authors.forename: Thach
authors.initials: T
authors.lastname: Chu
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06519-1612, USA.
authors.forename: Anne Marie
authors.initials: AM
authors.lastname: Rhebergen
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06519-1612, USA.
authors.forename: Vikram
authors.initials: V
authors.lastname: Jairam
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06519-1612, USA.
authors.forename: Nika
authors.initials: N
authors.lastname: Cyrus
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06519-1612, USA.
authors.forename: Carolyn E
authors.initials: CE
authors.lastname: Brokowski
authors.affiliation: 1] Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06519-1612, USA [2] Department of Laboratory Medicine, Yale University School of Medicine, New Haven, Connecticut 06520-8035, USA.
authors.forename: Stephanie C
authors.initials: SC
authors.lastname: Eisenbarth
authors.affiliation: Department of Chemistry, Yale University School of Medicine, New Haven, Connecticut 06520-8107, USA.
authors.forename: Gillian M
authors.initials: GM
authors.lastname: Phillips
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520-8020, USA.
authors.forename: Gary W
authors.initials: GW
authors.lastname: Cline
authors.affiliation: Department of Chemistry, Yale University School of Medicine, New Haven, Connecticut 06520-8107, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Phillips
authors.affiliation: 1] Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06519-1612, USA [2] Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut 06520-8028, USA [3] Howard Hughes Medical Institute, Chevy Chase, Maryland 20815-6789, USA.
authors.forename: Ruslan
authors.initials: R
authors.lastname: Medzhitov
mesh_terms: D000818:Animals; D001119:Arginase / Q000235:genetics / Q000378:metabolism; D018827:Carcinoma, Lewis Lung / Q000473:pathology; D002450:Cell Communication / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D017077:Culture Media, Conditioned / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D006019:Glycolysis; D006706:Homeostasis; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism* / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D008546:Melanoma, Experimental / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D012995:Solubility; D015854:Up-Regulation / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D017077:Culture Media, Conditioned; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D019344:Lactic Acid; D001119:Arginase