title: Targeting the ANG2/TIE2 axis inhibits tumor growth and metastasis by impairing angiogenesis and disabling rebounds of proangiogenic myeloid cells.
abstract: 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.
authors.affiliation: Angiogenesis and Tumor Targeting Research Unit, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Mazzieri
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Pucci
authors.forename: Davide
authors.initials: D
authors.lastname: Moi
authors.forename: Erika
authors.initials: E
authors.lastname: Zonari
authors.forename: Anna
authors.initials: A
authors.lastname: Ranghetti
authors.forename: Alvise
authors.initials: A
authors.lastname: Berti
authors.forename: Letterio S
authors.initials: LS
authors.lastname: Politi
authors.forename: Bernhard
authors.initials: B
authors.lastname: Gentner
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Brown
authors.forename: Luigi
authors.initials: L
authors.lastname: Naldini
authors.forename: Michele
authors.initials: M
authors.lastname: De Palma
mesh_terms: D007516:Adenoma, Islet Cell; D042702:Angiopoietin-2 / Q000037:antagonists & inhibitors / Q000502:physiology*; D000818:Animals; D002450:Cell Communication; D042783:Endothelial Cells / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008264:Macrophages / Q000502:physiology; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000502:physiology*; D009362:Neoplasm Metastasis / Q000517:prevention & control; D009374:Neoplasms, Experimental / Q000098:blood supply* / Q000517:prevention & control*; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D018358:Neuroendocrine Tumors / Q000517:prevention & control; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D042787:Receptor, TIE-2
chemical_list: D042702:Angiopoietin-2; D020794:Receptor Protein-Tyrosine Kinases; D042787:Receptor, TIE-2; C079086:Tek protein, mouse