Macrophage Metabolism Controls Tumor Blood Vessel Morphogenesis and Metastasis

Cell Metab. 2016 Nov 8;24(5):701-715. doi: 10.1016/j.cmet.2016.09.008. Epub 2016 Oct 20.


Hypoxic tumor-associated macrophages (TAMs) acquire angiogenic and immunosuppressive properties. Yet it remains unknown if metabolic changes influence these functions. Here, we argue that hypoxic TAMs strongly upregulate the expression of REDD1, a negative regulator of mTOR. REDD1-mediated mTOR inhibition hinders glycolysis in TAMs and curtails their excessive angiogenic response, with consequent formation of abnormal blood vessels. Accordingly, REDD1 deficiency in TAMs leads to the formation of smoothly aligned, pericyte-covered, functional vessels, which prevents vessel leakiness, hypoxia, and metastases. Mechanistically, highly glycolytic REDD1-deficient TAMs outcompete endothelial cells for glucose usage that thwarts vascular hyperactivation and promotes the formation of quiescent vascular junctions. Tuning down glycolysis in REDD1 knockout TAMs re-establishes abnormal angiogenesis and metastases. On this basis, we prove that the anti-tumor effect of mTOR inhibitors is partly countered by the deleterious outcome of these drugs on TAMs. Our data provide a functional link between TAM metabolism and tumor angiogenesis.

Keywords: angiogenesis; cancer; metabolism; metastasis; tumor-associated macrophages.

MeSH terms

  • Animals
  • Blood Vessels / growth & development*
  • Blood Vessels / metabolism
  • Cell Hypoxia
  • Disease Models, Animal
  • Endothelial Cells / metabolism
  • Gene Deletion
  • Glucose / metabolism
  • Glycolysis
  • Macrophages / metabolism*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Morphogenesis*
  • Neoplasm Metastasis
  • Neoplasms / blood supply*
  • Neoplasms / metabolism*
  • Neoplasms / pathology
  • Neovascularization, Pathologic / metabolism*
  • Signal Transduction
  • TOR Serine-Threonine Kinases / metabolism
  • Transcription Factors / metabolism
  • Up-Regulation


  • Ddit4 protein, mouse
  • Transcription Factors
  • TOR Serine-Threonine Kinases
  • Glucose