Role of angiopoietin-2 in adaptive tumor resistance to VEGF signaling blockade

Cell Rep. 2014 Aug 7;8(3):696-706. doi: 10.1016/j.celrep.2014.06.059. Epub 2014 Jul 31.


Angiopoietin-2 (ANG2/ANGPT2) is a context-dependent TIE2 receptor agonist/antagonist and proangiogenic factor. Although ANG2 neutralization improves tumor angiogenesis and growth inhibition by vascular endothelial growth factor (VEGF)-A signaling blockade, the mechanistic underpinnings of such therapeutic benefits remain poorly explored. We employed late-stage RIP1-Tag2 pancreatic neuroendocrine tumors (PNETs) and MMTV-PyMT mammary adenocarcinomas, which develop resistance to VEGF receptor 2 (VEGFR2) blockade. We found that VEGFR2 inhibition upregulated ANG2 and vascular TIE2 and enhanced infiltration by TIE2-expressing macrophages in the PNETs. Dual ANG2/VEGFR2 blockade suppressed revascularization and progression in most of the PNETs, whereas it had only minor additive effects in the mammary tumors, which did not upregulate ANG2 upon VEGFR2 inhibition. ANG2/VEGFR2 blockade did not elicit increased PNET invasion and metastasis, although it exacerbated tumor hypoxia and hematopoietic cell infiltration. These findings suggest that evasive tumor resistance to anti-VEGFA therapy may involve the adaptive enforcement of ANG2-TIE2 signaling, which can be reversed by ANG2 neutralization.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / drug therapy
  • Adenocarcinoma / metabolism*
  • Animals
  • Antibodies, Monoclonal / pharmacology
  • Antibodies, Monoclonal / therapeutic use
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / metabolism*
  • Drug Resistance, Neoplasm*
  • Macrophages / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Pancreatic Neoplasms / drug therapy
  • Pancreatic Neoplasms / metabolism*
  • Ribonuclease, Pancreatic / antagonists & inhibitors
  • Ribonuclease, Pancreatic / immunology
  • Ribonuclease, Pancreatic / metabolism*
  • Signal Transduction
  • Up-Regulation
  • Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors
  • Vascular Endothelial Growth Factor Receptor-2 / immunology
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism*


  • Antibodies, Monoclonal
  • Antineoplastic Agents
  • Kdr protein, mouse
  • Vascular Endothelial Growth Factor Receptor-2
  • Ang2 protein, mouse
  • Ribonuclease, Pancreatic