Targeting vascular pericytes in hypoxic tumors increases lung metastasis via angiopoietin-2

Cell Rep. 2015 Feb 24;10(7):1066-81. doi: 10.1016/j.celrep.2015.01.035. Epub 2015 Feb 19.


Strategies to target angiogenesis include inhibition of the vessel-stabilizing properties of vascular pericytes. Pericyte depletion in early-stage non-hypoxic tumors suppressed nascent angiogenesis, tumor growth, and lung metastasis. In contrast, pericyte depletion in advanced-stage hypoxic tumors with pre-established vasculature resulted in enhanced intra-tumoral hypoxia, decreased tumor growth, and increased lung metastasis. Furthermore, depletion of pericytes in post-natal retinal blood vessels resulted in abnormal and leaky vasculature. Tumor transcriptome profiling and biological validation revealed that angiopoietin signaling is a key regulatory pathway associated with pericyte targeting. Indeed, pericyte targeting in established mouse tumors increased angiopoietin-2 (ANG2/Angpt2) expression. Depletion of pericytes, coupled with targeting of ANG2 signaling, restored vascular stability in multiple model systems and decreased tumor growth and metastasis. Importantly, ANGPT2 expression correlated with poor outcome in patients with breast cancer. These results emphasize the potential utility of therapeutic regimens that target pericytes and ANG2 signaling in metastatic breast cancer.

Publication types

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

MeSH terms

  • Angiopoietin-2 / immunology
  • Angiopoietin-2 / metabolism*
  • Animals
  • Antibodies / immunology
  • Antibodies / pharmacology
  • Antigens / genetics
  • Antigens / metabolism
  • Breast Neoplasms / pathology*
  • Cell Hypoxia
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Epithelial-Mesenchymal Transition
  • Female
  • Imatinib Mesylate / pharmacology
  • Lung Neoplasms / pathology
  • Lung Neoplasms / secondary*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Neovascularization, Pathologic
  • Pericytes / cytology
  • Pericytes / drug effects
  • Pericytes / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • Proteoglycans / deficiency
  • Proteoglycans / genetics
  • Proteoglycans / metabolism
  • Receptor, Platelet-Derived Growth Factor beta / deficiency
  • Receptor, Platelet-Derived Growth Factor beta / genetics
  • Receptor, Platelet-Derived Growth Factor beta / metabolism
  • Retina / physiology
  • Signal Transduction / drug effects


  • Angiopoietin-2
  • Antibodies
  • Antigens
  • Protein Kinase Inhibitors
  • Proteoglycans
  • chondroitin sulfate proteoglycan 4
  • Imatinib Mesylate
  • Receptor, Platelet-Derived Growth Factor beta