title: PAI-1 mediates the antiangiogenic and profibrinolytic effects of 16K prolactin.
abstract: The N-terminal fragment of prolactin (16K PRL) inhibits tumor growth by impairing angiogenesis, but the underlying mechanisms are unknown. Here, we found that 16K PRL binds the fibrinolytic inhibitor plasminogen activator inhibitor-1 (PAI-1), which is known to contextually promote tumor angiogenesis and growth. Loss of PAI-1 abrogated the antitumoral and antiangiogenic effects of 16K PRL. PAI-1 bound the ternary complex PAI-1-urokinase-type plasminogen activator (uPA)-uPA receptor (uPAR), thereby exerting antiangiogenic effects. By inhibiting the antifibrinolytic activity of PAI-1, 16K PRL also protected mice against thromboembolism and promoted arterial clot lysis. Thus, by signaling through the PAI-1-uPA-uPAR complex, 16K PRL impairs tumor vascularization and growth and, by inhibiting the antifibrinolytic activity of PAI-1, promotes thrombolysis.
authors.affiliation: 1] Molecular Angiogenesis Laboratory, Interdisciplinary Cluster in Applied Genoproteomics (GIGA) Research Center, University of Liège, Liège, Belgium. [2].
authors.forename: Khalid
authors.initials: K
authors.lastname: Bajou
authors.affiliation: 1] Molecular Angiogenesis Laboratory, Interdisciplinary Cluster in Applied Genoproteomics (GIGA) Research Center, University of Liège, Liège, Belgium. [2].
authors.forename: Stephanie
authors.initials: S
authors.lastname: Herkenne
authors.affiliation: 1] Angiogenesis Laboratory, Department of Medical Oncology, VU University Medical Center, Amsterdam, the Netherlands. [2] Department of Radiotherapy, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Victor L
authors.identifier: 0000000261461842
authors.initials: VL
authors.lastname: Thijssen
authors.affiliation: Molecular Angiogenesis Laboratory, Interdisciplinary Cluster in Applied Genoproteomics (GIGA) Research Center, University of Liège, Liège, Belgium.
authors.forename: Salvino
authors.initials: S
authors.lastname: D'Amico
authors.affiliation: Molecular Angiogenesis Laboratory, Interdisciplinary Cluster in Applied Genoproteomics (GIGA) Research Center, University of Liège, Liège, Belgium.
authors.forename: Ngoc-Quynh-Nhu
authors.initials: NQ
authors.lastname: Nguyen
authors.affiliation: 1] Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center (VRC), VIB, Leuven, Belgium. [2] Laboratory of Angiogenesis & Neurovascular Link, Department of Oncology, KU Leuven, Leuven, Belgium.
authors.forename: Ann
authors.initials: A
authors.lastname: Bouché
authors.affiliation: Molecular Angiogenesis Laboratory, Interdisciplinary Cluster in Applied Genoproteomics (GIGA) Research Center, University of Liège, Liège, Belgium.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Tabruyn
authors.affiliation: Molecular Angiogenesis Laboratory, Interdisciplinary Cluster in Applied Genoproteomics (GIGA) Research Center, University of Liège, Liège, Belgium.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Srahna
authors.affiliation: Molecular Angiogenesis Laboratory, Interdisciplinary Cluster in Applied Genoproteomics (GIGA) Research Center, University of Liège, Liège, Belgium.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Carabin
authors.affiliation: Molecular Angiogenesis Laboratory, Interdisciplinary Cluster in Applied Genoproteomics (GIGA) Research Center, University of Liège, Liège, Belgium.
authors.forename: Olivier
authors.initials: O
authors.lastname: Nivelles
authors.affiliation: Molecular Angiogenesis Laboratory, Interdisciplinary Cluster in Applied Genoproteomics (GIGA) Research Center, University of Liège, Liège, Belgium.
authors.forename: Cécile
authors.initials: C
authors.lastname: Paques
authors.affiliation: 1] Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center (VRC), VIB, Leuven, Belgium. [2] Laboratory of Angiogenesis & Neurovascular Link, Department of Oncology, KU Leuven, Leuven, Belgium.
authors.forename: Ivo
authors.initials: I
authors.lastname: Cornelissen
authors.affiliation: Molecular Angiogenesis Laboratory, Interdisciplinary Cluster in Applied Genoproteomics (GIGA) Research Center, University of Liège, Liège, Belgium.
authors.forename: Michelle
authors.initials: M
authors.lastname: Lion
authors.affiliation: Unit of Biology of Tumor and Development, GIGA Research Center, University of Liège, Liège, Belgium.
authors.forename: Agnès
authors.initials: A
authors.lastname: Noel
authors.affiliation: Laboratory for Therapeutic and Diagnostic Antibodies, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium.
authors.forename: Ann
authors.initials: A
authors.lastname: Gils
authors.affiliation: 1] Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center (VRC), VIB, Leuven, Belgium. [2] Laboratory of Angiogenesis & Neurovascular Link, Department of Oncology, KU Leuven, Leuven, Belgium.
authors.forename: Stefan
authors.initials: S
authors.lastname: Vinckier
authors.affiliation: Laboratory for Therapeutic and Diagnostic Antibodies, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Declerck
authors.affiliation: Angiogenesis Laboratory, Department of Medical Oncology, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Arjan W
authors.initials: AW
authors.lastname: Griffioen
authors.affiliation: 1] Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center (VRC), VIB, Leuven, Belgium. [2] Laboratory of Angiogenesis & Neurovascular Link, Department of Oncology, KU Leuven, Leuven, Belgium.
authors.forename: Mieke
authors.initials: M
authors.lastname: Dewerchin
authors.affiliation: 1] Molecular Angiogenesis Laboratory, Interdisciplinary Cluster in Applied Genoproteomics (GIGA) Research Center, University of Liège, Liège, Belgium. [2].
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Martial
authors.affiliation: 1] Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center (VRC), VIB, Leuven, Belgium. [2] Laboratory of Angiogenesis & Neurovascular Link, Department of Oncology, KU Leuven, Leuven, Belgium. [3].
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
authors.affiliation: Molecular Angiogenesis Laboratory, Interdisciplinary Cluster in Applied Genoproteomics (GIGA) Research Center, University of Liège, Liège, Belgium.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Struman
mesh_terms: D000818:Animals; D002455:Cell Division; D002478:Cells, Cultured; D005342:Fibrinolysis; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000098:blood supply / Q000473:pathology; D009389:Neovascularization, Pathologic; D010446:Peptide Fragments / Q000737:chemistry / Q000502:physiology; D017395:Plasminogen Activator Inhibitor 1 / Q000502:physiology*; D011388:Prolactin / Q000737:chemistry / Q000502:physiology*
chemical_list: D010446:Peptide Fragments; D017395:Plasminogen Activator Inhibitor 1; D011388:Prolactin