title: Targeting the lactate transporter MCT1 in endothelial cells inhibits lactate-induced HIF-1 activation and tumor angiogenesis.
abstract: Switching to a glycolytic metabolism is a rapid adaptation of tumor cells to hypoxia. Although this metabolic conversion may primarily represent a rescue pathway to meet the bioenergetic and biosynthetic demands of proliferating tumor cells, it also creates a gradient of lactate that mirrors the gradient of oxygen in tumors. More than a metabolic waste, the lactate anion is known to participate to cancer aggressiveness, in part through activation of the hypoxia-inducible factor-1 (HIF-1) pathway in tumor cells. Whether lactate may also directly favor HIF-1 activation in endothelial cells (ECs) thereby offering a new druggable option to block angiogenesis is however an unanswered question. In this study, we therefore focused on the role in ECs of monocarboxylate transporter 1 (MCT1) that we previously identified to be the main facilitator of lactate uptake in cancer cells. We found that blockade of lactate influx into ECs led to inhibition of HIF-1-dependent angiogenesis. Our demonstration is based on the unprecedented characterization of lactate-induced HIF-1 activation in normoxic ECs and the consecutive increase in vascular endothelial growth factor receptor 2 (VEGFR2) and basic fibroblast growth factor (bFGF) expression. Furthermore, using a variety of functional assays including endothelial cell migration and tubulogenesis together with in vivo imaging of tumor angiogenesis through intravital microscopy and immunohistochemistry, we documented that MCT1 blockers could act as bona fide HIF-1 inhibitors leading to anti-angiogenic effects. Together with the previous demonstration of MCT1 being a key regulator of lactate exchange between tumor cells, the current study identifies MCT1 inhibition as a therapeutic modality combining antimetabolic and anti-angiogenic activities.
authors.affiliation: Pole of Pharmacology, Institute of Experimental and Clinical Research, Université Catholique de Louvain, Brussels, Belgium. pierre.sonveaux@uclouvain.be
authors.forename: Pierre
authors.initials: P
authors.lastname: Sonveaux
authors.forename: Tamara
authors.initials: T
authors.lastname: Copetti
authors.forename: Christophe J
authors.initials: CJ
authors.lastname: De Saedeleer
authors.forename: Frédérique
authors.initials: F
authors.lastname: Végran
authors.forename: Julien
authors.initials: J
authors.lastname: Verrax
authors.forename: Kelly M
authors.initials: KM
authors.lastname: Kennedy
authors.forename: Eui Jung
authors.initials: EJ
authors.lastname: Moon
authors.forename: Suveera
authors.initials: S
authors.lastname: Dhup
authors.forename: Pierre
authors.initials: P
authors.lastname: Danhier
authors.forename: Françoise
authors.initials: F
authors.lastname: Frérart
authors.forename: Bernard
authors.initials: B
authors.lastname: Gallez
authors.forename: Anthony
authors.initials: A
authors.lastname: Ribeiro
authors.forename: Carine
authors.initials: C
authors.lastname: Michiels
authors.forename: Mark W
authors.initials: MW
authors.lastname: Dewhirst
authors.forename: Olivier
authors.initials: O
authors.lastname: Feron
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D002465:Cell Movement / Q000502:physiology; D042783:Endothelial Cells / Q000378:metabolism* / Q000502:physiology; D004797:Enzyme-Linked Immunosorbent Assay; D005346:Fibroblast Growth Factors / Q000378:metabolism; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D007150:Immunohistochemistry; D019344:Lactic Acid / Q000378:metabolism* / Q000494:pharmacology; D008156:Luciferases; D051379:Mice; D027501:Monocarboxylic Acid Transporters / Q000378:metabolism*; D009369:Neoplasms / Q000098:blood supply*; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D019906:Nuclear Magnetic Resonance, Biomolecular; D016133:Polymerase Chain Reaction; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D027981:Symporters / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D000099233:Monocarboxylate Transport Protein 1
chemical_list: D005346:Fibroblast Growth Factors; D051793:Hypoxia-Inducible Factor 1; D019344:Lactic Acid; D008156:Luciferases; D027501:Monocarboxylic Acid Transporters; D034741:RNA, Small Interfering; D027981:Symporters; D040301:Vascular Endothelial Growth Factor Receptor-2; D000099233:Monocarboxylate Transport Protein 1; C108111:fibroblast growth factor 13