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

Nature volume 513, pages 559563 (25 September 2014) | Download Citation



Macrophages have an important role in the maintenance of tissue homeostasis1. 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 composition2. Similarly to macrophages in normal tissues and organs, macrophages in tumours (tumour-associated macrophages) perform some key homeostatic functions that allow tumour maintenance and growth3,4,5. 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.

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  1. 1.

    Trophic macrophages in development and disease. Nature Rev. Immunol. 9, 259–270 (2009)

  2. 2.

    , & Tumors as organs: complex tissues that interface with the entire organism. Dev. Cell 18, 884–901 (2010)

  3. 3.

    , & Immunity, inflammation, and cancer. Cell 140, 883–899 (2010)

  4. 4.

    , , & Cancer-related inflammation. Nature 454, 436–444 (2008)

  5. 5.

    & Macrophage diversity enhances tumor progression and metastasis. Cell 141, 39–51 (2010)

  6. 6.

    , & Macrophage arginase promotes tumor cell growth and suppresses nitric oxide-mediated tumor cytotoxicity. Cancer Res. 61, 1100–1106 (2001)

  7. 7.

    , , & Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 359, 843–845 (1992)

  8. 8.

    & Alternative activation of macrophages: mechanism and functions. Immunity 32, 593–604 (2010)

  9. 9.

    et al. HIF-independent regulation of VEGF and angiogenesis by the transcriptional coactivator PGC-1α. Nature 451, 1008–1012 (2008)

  10. 10.

    , & Hypoxia-inducible factor 1 activation by aerobic glycolysis implicates the Warburg effect in carcinogenesis. J. Biol. Chem. 277, 23111–23115 (2002)

  11. 11.

    et al. Adenosine A2a receptor-mediated, normoxic induction of HIF-1 through PKC and PI-3K-dependent pathways in macrophages. J. Leukoc. Biol. 82, 392–402 (2007)

  12. 12.

    , , & HIF activation by pH-dependent nucleolar sequestration of VHL. Nature Cell Biol. 6, 642–647 (2004)

  13. 13.

    On the origin of cancer cells. Science 123, 309–314 (1956)

  14. 14.

    , & Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324, 1029–1033 (2009)

  15. 15.

    et al. The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature 452, 230–233 (2008)

  16. 16.

    & Protective and pathogenic functions of macrophage subsets. Nature Rev. Immunol. 11, 723–737 (2011)

  17. 17.

    et al. Macrophages regulate the angiogenic switch in a mouse model of breast cancer. Cancer Res. 66, 11238–11246 (2006)

  18. 18.

    Tumor angiogenesis: therapeutic implications. N. Engl. J. Med. 285, 1182–1186 (1971)

  19. 19.

    & Macrophages: master regulators of inflammation and fibrosis. Semin. Liver Dis. 30, 245–257 (2010)

  20. 20.

    et al. CD4+ T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages. Cancer Cell 16, 91–102 (2009)

  21. 21.

    et al. Carcinoma-produced factors activate myeloid cells through TLR2 to stimulate metastasis. Nature 457, 102–106 (2009)

  22. 22.

    et al. A paracrine loop between tumor cells and macrophages is required for tumor cell migration in mammary tumors. Cancer Res. 64, 7022–7029 (2004)

  23. 23.

    et al. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 88, 277–285 (1997)

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We thank members of the Medzhitov laboratory for discussions, L. Xu, C. Annicelli, S. Cronin and G. Tokmoulina for animal care and technical help, and N. Palm for critical feedback on the manuscript. O.R.C. is supported by the National Cancer Institute (1K08CA172580-01), the Yale Center for Clinical Investigation (5KL2RR024138), the Yale SPORE in Skin Cancer (1 P50 CA121974), the Damon Runyon Cancer Research Foundation (DRG 108-09) and the Dermatology Foundation. R.M.’s laboratory is supported by The Blavatnik Family Foundation, grants from the National Institutes of Health (AI046688, AI089771 and CA157461) and the Howard Hughes Medical Institute.

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  1. Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06519-1612, USA

    • Oscar R. Colegio
    • , Ngoc-Quynh Chu
    • , Alison L. Szabo
    • , Thach Chu
    • , Anne Marie Rhebergen
    • , Vikram Jairam
    • , Nika Cyrus
    • , Carolyn E. Brokowski
    • , Stephanie C. Eisenbarth
    •  & Ruslan Medzhitov
  2. Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut 06520-8059, USA

    • Oscar R. Colegio
  3. Yale-New Haven Transplantation Center, Yale University School of Medicine, New Haven, Connecticut 06519-1369, USA

    • Oscar R. Colegio
  4. Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut 06520-8028, USA

    • Oscar R. Colegio
    •  & Ruslan Medzhitov
  5. Department of Laboratory Medicine, Yale University School of Medicine, New Haven, Connecticut 06520-8035, USA

    • Stephanie C. Eisenbarth
  6. Department of Chemistry, Yale University School of Medicine, New Haven, Connecticut 06520-8107, USA

    • Gillian M. Phillips
    •  & Andrew J. Phillips
  7. Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520-8020, USA

    • Gary W. Cline
  8. Howard Hughes Medical Institute, Chevy Chase, Maryland 20815-6789, USA

    • Ruslan Medzhitov


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O.R.C. and R.M. conceived the project, designed the experimental approach, interpreted data and wrote the manuscript. N.-Q.C. and A.L.S. designed and performed experiments and wrote the manuscript. T.C., A.M.R., V.J., N.C., C.E.B., G.M.P. and G.W.C. designed and performed experiments and analysed data. S.C.E. and A.J.P. designed experiments, analysed data and provided key expertise.

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The authors declare no competing financial interests.

Corresponding author

Correspondence to Ruslan Medzhitov.

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