title: Overexpression of factor inhibiting HIF-1 enhances vessel maturation and tumor growth via platelet-derived growth factor-C.
abstract: Recent studies have revealed that the maturation state of vessels in tumors, in addition to vascularity, is a critical determinant of tumor growth. The role of oxygen-dependent signaling pathways in hypoxia-stimulated angiogenesis is well established, however, little is known about their impact on vessel maturation in tumors. Here, we have studied the function of the cellular oxygen sensor, factor inhibiting HIF-1 (FIH), which controls the activity of hypoxia-inducible factor-1. FIH silencing in mouse LM8 osteosarcoma stimulated angiogenesis but did not influence tumor growth. In contrast, FIH overexpression led to increased pericyte coverage of the tumor vasculature, reduced vessel leakiness and enhanced tumor growth. Vessel maturation was paralleled by up-regulation of platelet-derived growth factor (PDGF)-C in tumors and expression of PDGF receptor-α on pericytes. Ablation of PDGF-C in FIH-overexpressing tumor cells reduced pericyte coverage and tumor growth. Our data suggest that FIH-mediated PDGF-C induction in LM8 osteosarcoma stimulates the recruitment of PDGFR-α positive pericytes to the tumor vasculature, leading to vessel maturation and enhanced tumor growth.
authors.affiliation: Department of Pathology, University of Technology Dresden, Germany.
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Kuzmanov
authors.forename: Ben
authors.initials: B
authors.lastname: Wielockx
authors.forename: Maryam
authors.initials: M
authors.lastname: Rezaei
authors.forename: Antje
authors.initials: A
authors.lastname: Kettelhake
authors.forename: Georg
authors.initials: G
authors.lastname: Breier
mesh_terms: D043925:Angiogenesis Inducing Agents; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation; D005260:Female; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics / Q000378:metabolism; D007124:Immunoenzyme Techniques; D008222:Lymphokines / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008809:Mice, Inbred C3H; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000378:metabolism*; D009389:Neovascularization, Pathologic; D012516:Osteosarcoma / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology*; D020286:Pericytes / Q000378:metabolism / Q000473:pathology; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
chemical_list: D043925:Angiogenesis Inducing Agents; D051793:Hypoxia-Inducible Factor 1; D008222:Lymphokines; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C411423:platelet-derived growth factor C; D006899:Mixed Function Oxygenases; C551240:factor inhibiting hypoxia-inducible factor 1, mouse; D020796:Receptor, Platelet-Derived Growth Factor alpha