title: Role of angiopoietin-2 in adaptive tumor resistance to VEGF signaling blockade.
abstract: 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.
authors.affiliation: Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
authors.forename: Nicolò
authors.initials: N
authors.lastname: Rigamonti
authors.affiliation: Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
authors.forename: Ece
authors.initials: E
authors.lastname: Kadioglu
authors.affiliation: Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
authors.forename: Ioanna
authors.initials: I
authors.lastname: Keklikoglou
authors.affiliation: Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
authors.forename: Céline
authors.initials: C
authors.lastname: Wyser Rmili
authors.affiliation: Translational Medicine Oncology, MedImmune, Gaithersburg, MD 20878, USA.
authors.forename: Ching Ching
authors.initials: CC
authors.lastname: Leow
authors.affiliation: Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland. Electronic address: michele.depalma@epfl.ch.
authors.forename: Michele
authors.initials: M
authors.lastname: De Palma
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D012259:Ribonuclease, Pancreatic / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction; D015854:Up-Regulation; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; C000592875:Kdr protein, mouse; D040301:Vascular Endothelial Growth Factor Receptor-2; C099439:Ang2 protein, mouse; D012259:Ribonuclease, Pancreatic