Targeting the ANG2/TIE2 axis inhibits tumor growth and metastasis by impairing angiogenesis and disabling rebounds of proangiogenic myeloid cells

Cancer Cell. 2011 Apr 12;19(4):512-26. doi: 10.1016/j.ccr.2011.02.005.


Tumor-infiltrating myeloid cells convey proangiogenic programs that counteract the efficacy of antiangiogenic therapy. Here, we show that blocking angiopoietin-2 (ANG2), a TIE2 ligand and angiogenic factor expressed by activated endothelial cells (ECs), regresses the tumor vasculature and inhibits progression of late-stage, metastatic MMTV-PyMT mammary carcinomas and RIP1-Tag2 pancreatic insulinomas. ANG2 blockade did not inhibit recruitment of MRC1(+) TIE2-expressing macrophages (TEMs) but impeded their upregulation of Tie2, association with blood vessels, and ability to restore angiogenesis in tumors. Conditional Tie2 gene knockdown in TEMs was sufficient to decrease tumor angiogenesis. Our findings support a model wherein the ANG2-TIE2 axis mediates cell-to-cell interactions between TEMs and ECs that are important for tumor angiogenesis and can be targeted to induce effective antitumor responses.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoma, Islet Cell
  • Angiopoietin-2 / antagonists & inhibitors
  • Angiopoietin-2 / physiology*
  • Animals
  • Cell Communication
  • Endothelial Cells / physiology
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Macrophages / physiology
  • Mammary Neoplasms, Experimental / blood supply
  • Mammary Neoplasms, Experimental / pathology
  • Mammary Neoplasms, Experimental / prevention & control
  • Mice
  • Mice, Inbred C57BL
  • Myeloid Cells / physiology*
  • Neoplasm Metastasis / prevention & control
  • Neoplasms, Experimental / blood supply*
  • Neoplasms, Experimental / prevention & control*
  • Neovascularization, Pathologic / prevention & control*
  • Neuroendocrine Tumors / prevention & control
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors
  • Receptor Protein-Tyrosine Kinases / physiology*
  • Receptor, TIE-2


  • Angiopoietin-2
  • Receptor Protein-Tyrosine Kinases
  • Receptor, TIE-2
  • Tek protein, mouse