ArticleCancer cell2016
Inhibition of the Glycolytic Activator PFKFB3 in Endothelium Induces Tumor Vessel Normalization, Impairs Metastasis, and Improves Chemotherapy.
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Article in Cancer cell, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 392 papers, 1 of them a synthesis that pooled it.
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392citing papers in PubMed, 1 pooled it
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392 citing papers in PubMed, 1 synthesis or guideline pooled it, 648 citations in OpenAlex.
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332 more citing papers are in PubMed but not listed here.
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Authors and funding
34 authors at 5 institutions in 4 countries.
Anna Rita CantelmoLaboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven 3000, Belgium; Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, VIB, Leuven 3000, Belgium.
Lena-Christin ConradiLaboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven 3000, Belgium; Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, VIB, Leuven 3000, Belgium.
Aleksandra BrajicLaboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven 3000, Belgium; Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, VIB, Leuven 3000, Belgium.
Jermaine GoveiaLaboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven 3000, Belgium; Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, VIB, Leuven 3000, Belgium.
Joanna KaluckaLaboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven 3000, Belgium; Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, VIB, Leuven 3000, Belgium.
Andreas PircherLaboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven 3000, Belgium; Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, VIB, Leuven 3000, Belgium.
Pallavi ChaturvediDepartment of Pharmacology, University of Illinois College of Medicine, Chicago, IL 60612, USA.
Johanna HolDepartment of Pathology, K.G. Jebsen Inflammation Research Center, Oslo University Hospital, University of Oslo, Oslo 0424, Norway.
Bernard ThienpontLaboratory for Translational Genetics, Vesalius Research Center, VIB, Leuven 3000, Belgium; Laboratory for Translational Genetics, Department of Oncology, KU Leuven, Leuven 3000, Belgium.
Laure-Anne TeuwenLaboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven 3000, Belgium; Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, VIB, Leuven 3000, Belgium.
Sandra SchoorsLaboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven 3000, Belgium; Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, VIB, Leuven 3000, Belgium.
Bram BoeckxLaboratory for Translational Genetics, Vesalius Research Center, VIB, Leuven 3000, Belgium; Laboratory for Translational Genetics, Department of Oncology, KU Leuven, Leuven 3000, Belgium.
Joris VriensLaboratory of Ion Channel Research and TRP Research Platform Leuven (TRPLe), KU Leuven, Leuven 3000, Belgium.
Anna KuchnioLaboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven 3000, Belgium; Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, VIB, Leuven 3000, Belgium.
Koen VeysLaboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven 3000, Belgium; Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, VIB, Leuven 3000, Belgium.
Bert CruysLaboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven 3000, Belgium; Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, VIB, Leuven 3000, Belgium.
Lise FinottoLaboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven 3000, Belgium; Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, VIB, Leuven 3000, Belgium.
Lucas TrepsLaboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven 3000, Belgium; Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, VIB, Leuven 3000, Belgium.
Tor Espen Stav-NoraasDepartment of Pathology, K.G. Jebsen Inflammation Research Center, Oslo University Hospital, University of Oslo, Oslo 0424, Norway.
Francesco BifariLaboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven 3000, Belgium; Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, VIB, Leuven 3000, Belgium.
Peter StaporLaboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven 3000, Belgium; Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, VIB, Leuven 3000, Belgium.
Ilaria DecimoLaboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven 3000, Belgium; Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, VIB, Leuven 3000, Belgium.
Kim KampenLaboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven 3000, Belgium; Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, VIB, Leuven 3000, Belgium.
Katrien De BockLaboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven 3000, Belgium; Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, VIB, Leuven 3000, Belgium.
Guttorm HaraldsenDepartment of Pathology, K.G. Jebsen Inflammation Research Center, Oslo University Hospital, University of Oslo, Oslo 0424, Norway.
Luc SchoonjansLaboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven 3000, Belgium; Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, VIB, Leuven 3000, Belgium.
Ton RabelinkDepartment of Nephrology, Einthoven Laboratory for Vascular Medicine, LUMC, Leiden University Medical Center, Leiden 2300 RC, the Netherlands.
Guy EelenLaboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven 3000, Belgium; Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, VIB, Leuven 3000, Belgium.
Bart GhesquièreMetabolomics Core Facility, Department of Oncology, KU Leuven, Leuven 3000, Belgium; Metabolomics Core Facility, Vesalius Research Center, VIB, Leuven 3000, Belgium.
Jalees RehmanDepartment of Pharmacology, University of Illinois College of Medicine, Chicago, IL 60612, USA; Section of Cardiology, Department of Medicine, University of Illinois College of Medicine, Chicago, IL 60612, USA.
Diether LambrechtsLaboratory for Translational Genetics, Vesalius Research Center, VIB, Leuven 3000, Belgium; Laboratory for Translational Genetics, Department of Oncology, KU Leuven, Leuven 3000, Belgium.
Asrar B MalikDepartment of Pharmacology, University of Illinois College of Medicine, Chicago, IL 60612, USA.
Mieke DewerchinLaboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven 3000, Belgium; Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, VIB, Leuven 3000, Belgium.
Peter CarmelietLaboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven 3000, Belgium; Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, VIB, Leuven 3000, Belgium. Electronic address: peter.carmeliet@vib-kuleuven.be.
VIB-KU Leuven Center for Cancer Biology · BEOslo University Hospital · NOUniversity of Illinois Urbana-Champaign · USKU Leuven · BELeiden University Medical Center · NL
Funding
TRPC6 Regulation of Lung Endothelial Barrier FunctionP01HL060678 · NHLBI · UNIVERSITY OF ILLINOIS AT CHICAGO · PI MALIK, ASRAR B. · 2000 to 2020
$40.1MTRAINING PROGRAM IN LUNG BIOLOGY AND PATHOBIOLOGYT32HL007829 · NHLBI · UNIVERSITY OF ILLINOIS AT CHICAGO · PI DOLLY MEHTA · 1995 to 2026
$15.6MTHROMBIN-INDUCED PULMONARY VASCULAR PERMEABILITYR01HL045638 · NHLBI · UNIVERSITY OF ILLINOIS AT CHICAGO · PI KOMAROVA, YULIA A · 1991 to 2025
$12.0MMesenchymal-Endothelial Transition as a Homeostatic Regenerative Mechanism in Acute Lung InjuryR01HL090152 · NHLBI · UNIVERSITY OF ILLINOIS AT CHICAGO · PI MALIK, ASRAR B., REHMAN, JALEES · 2007 to 2019
$5.9MEndothelial Regeneration Following Lung Vascular InjuryR01HL118068 · NHLBI · UNIVERSITY OF ILLINOIS AT CHICAGO · PI MALIK, ASRAR B., REHMAN, JALEES · 2014 to 2017
$2.4MThe role of mitochondria in embryonic stem cells.R01GM094220 · NIGMS · UNIVERSITY OF ILLINOIS AT CHICAGO · PI REHMAN, JALEES · 2011 to 2015
$1.5MAustrian Science Fund FWF J 3730NHLBI NIH HHS P01 HL060678NHLBI NIH HHS R01 HL045638NHLBI NIH HHS R01 HL090152NHLBI NIH HHS R01 HL118068NHLBI NIH HHS T32 HL007829NIGMS NIH HHS R01 GM094220
Abstract
Abnormal tumor vessels promote metastasis and impair chemotherapy. Hence, tumor vessel normalization (TVN) is emerging as an anti-cancer treatment. Here, we show that tumor endothelial cells (ECs) have a hyper-glycolytic metabolism, shunting intermediates to nucleotide synthesis. EC haplo-deficiency or blockade of the glycolytic activator PFKFB3 did not affect tumor growth, but reduced cancer cell invasion, intravasation, and metastasis by normalizing tumor vessels, which improved vessel maturation and perfusion. Mechanistically, PFKFB3 inhibition tightened the vascular barrier by reducing VE-cadherin endocytosis in ECs, and rendering pericytes more quiescent and adhesive (via upregulation of N-cadherin) through glycolysis reduction; it also lowered the expression of cancer cell adhesion molecules in ECs by decreasing NF-κB signaling. PFKFB3-blockade treatment also improved chemotherapy of primary and metastatic tumors.
Indexed as
AnimalsCadherinsCell Line, TumorCell MovementCisplatinDrug SynergismDrug TherapyEpithelial CellsGene Expression Regulation, NeoplasticGlycolysisHumansHuman Umbilical Vein Endothelial CellsMiceNeoplasm InvasivenessNeoplasm MetastasisNeoplasmsCadherinsCdh2 protein, mouseCisplatinPFKFB3 protein, humanPhosphofructokinase-2Tamoxifenangiogenesischemotherapyglycolysismetastasistumor endothelial cell metabolismtumor vessel normalization
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