title: Inhibition of the Glycolytic Activator PFKFB3 in Endothelium Induces Tumor Vessel Normalization, Impairs Metastasis, and Improves Chemotherapy.
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.
authors.affiliation: Laboratory 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.
authors.forename: Anna Rita
authors.initials: AR
authors.lastname: Cantelmo
authors.affiliation: Laboratory 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.
authors.forename: Lena-Christin
authors.initials: LC
authors.lastname: Conradi
authors.affiliation: Laboratory 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.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Brajic
authors.affiliation: Laboratory 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.
authors.forename: Jermaine
authors.initials: J
authors.lastname: Goveia
authors.affiliation: Laboratory 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.
authors.forename: Joanna
authors.initials: J
authors.lastname: Kalucka
authors.affiliation: Laboratory 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.
authors.forename: Andreas
authors.initials: A
authors.lastname: Pircher
authors.affiliation: Department of Pharmacology, University of Illinois College of Medicine, Chicago, IL 60612, USA.
authors.forename: Pallavi
authors.initials: P
authors.lastname: Chaturvedi
authors.affiliation: Department of Pathology, K.G. Jebsen Inflammation Research Center, Oslo University Hospital, University of Oslo, Oslo 0424, Norway.
authors.forename: Johanna
authors.initials: J
authors.lastname: Hol
authors.affiliation: Laboratory for Translational Genetics, Vesalius Research Center, VIB, Leuven 3000, Belgium; Laboratory for Translational Genetics, Department of Oncology, KU Leuven, Leuven 3000, Belgium.
authors.forename: Bernard
authors.initials: B
authors.lastname: Thienpont
authors.affiliation: Laboratory 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.
authors.forename: Laure-Anne
authors.initials: LA
authors.lastname: Teuwen
authors.affiliation: Laboratory 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.
authors.forename: Sandra
authors.initials: S
authors.lastname: Schoors
authors.affiliation: Laboratory for Translational Genetics, Vesalius Research Center, VIB, Leuven 3000, Belgium; Laboratory for Translational Genetics, Department of Oncology, KU Leuven, Leuven 3000, Belgium.
authors.forename: Bram
authors.initials: B
authors.lastname: Boeckx
authors.affiliation: Laboratory of Ion Channel Research and TRP Research Platform Leuven (TRPLe), KU Leuven, Leuven 3000, Belgium.
authors.forename: Joris
authors.initials: J
authors.lastname: Vriens
authors.affiliation: Laboratory 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.
authors.forename: Anna
authors.initials: A
authors.lastname: Kuchnio
authors.affiliation: Laboratory 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.
authors.forename: Koen
authors.initials: K
authors.lastname: Veys
authors.affiliation: Laboratory 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.
authors.forename: Bert
authors.initials: B
authors.lastname: Cruys
authors.affiliation: Laboratory 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.
authors.forename: Lise
authors.initials: L
authors.lastname: Finotto
authors.affiliation: Laboratory 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.
authors.forename: Lucas
authors.initials: L
authors.lastname: Treps
authors.affiliation: Department of Pathology, K.G. Jebsen Inflammation Research Center, Oslo University Hospital, University of Oslo, Oslo 0424, Norway.
authors.forename: Tor Espen
authors.initials: TE
authors.lastname: Stav-Noraas
authors.affiliation: Laboratory 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.
authors.forename: Francesco
authors.initials: F
authors.lastname: Bifari
authors.affiliation: Laboratory 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.
authors.forename: Peter
authors.initials: P
authors.lastname: Stapor
authors.affiliation: Laboratory 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.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Decimo
authors.affiliation: Laboratory 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.
authors.forename: Kim
authors.initials: K
authors.lastname: Kampen
authors.affiliation: Laboratory 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.
authors.forename: Katrien
authors.initials: K
authors.lastname: De Bock
authors.affiliation: Department of Pathology, K.G. Jebsen Inflammation Research Center, Oslo University Hospital, University of Oslo, Oslo 0424, Norway.
authors.forename: Guttorm
authors.initials: G
authors.lastname: Haraldsen
authors.affiliation: Laboratory 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.
authors.forename: Luc
authors.initials: L
authors.lastname: Schoonjans
authors.affiliation: Department of Nephrology, Einthoven Laboratory for Vascular Medicine, LUMC, Leiden University Medical Center, Leiden 2300 RC, the Netherlands.
authors.forename: Ton
authors.initials: T
authors.lastname: Rabelink
authors.affiliation: Laboratory 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.
authors.forename: Guy
authors.initials: G
authors.lastname: Eelen
authors.affiliation: Metabolomics Core Facility, Department of Oncology, KU Leuven, Leuven 3000, Belgium; Metabolomics Core Facility, Vesalius Research Center, VIB, Leuven 3000, Belgium.
authors.forename: Bart
authors.initials: B
authors.lastname: Ghesquière
authors.affiliation: Department 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.
authors.forename: Jalees
authors.initials: J
authors.lastname: Rehman
authors.affiliation: Laboratory for Translational Genetics, Vesalius Research Center, VIB, Leuven 3000, Belgium; Laboratory for Translational Genetics, Department of Oncology, KU Leuven, Leuven 3000, Belgium.
authors.forename: Diether
authors.initials: D
authors.lastname: Lambrechts
authors.affiliation: Department of Pharmacology, University of Illinois College of Medicine, Chicago, IL 60612, USA.
authors.forename: Asrar B
authors.initials: AB
authors.lastname: Malik
authors.affiliation: Laboratory 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.
authors.forename: Mieke
authors.initials: M
authors.lastname: Dewerchin
authors.affiliation: Laboratory 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.
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
mesh_terms: D000818:Animals; D015820:Cadherins / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage* / Q000494:pharmacology; D004357:Drug Synergism; D004358:Drug Therapy; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006019:Glycolysis / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051379:Mice; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism*; D025481:Phosphofructokinase-2 / Q000037:antagonists & inhibitors*; D013629:Tamoxifen / Q000008:administration & dosage* / Q000494:pharmacology
chemical_list: D015820:Cadherins; C489083:Cdh2 protein, mouse; D013629:Tamoxifen; C107345:PFKFB3 protein, human; D025481:Phosphofructokinase-2; D002945:Cisplatin
keywords: angiogenesis; chemotherapy; glycolysis; metastasis; tumor endothelial cell metabolism; tumor vessel normalization