title: Heterozygous deficiency of PHD2 restores tumor oxygenation and inhibits metastasis via endothelial normalization.
abstract: A key function of blood vessels, to supply oxygen, is impaired in tumors because of abnormalities in their endothelial lining. PHD proteins serve as oxygen sensors and may regulate oxygen delivery. We therefore studied the role of endothelial PHD2 in vessel shaping by implanting tumors in PHD2(+/-) mice. Haplodeficiency of PHD2 did not affect tumor vessel density or lumen size, but normalized the endothelial lining and vessel maturation. This resulted in improved tumor perfusion and oxygenation and inhibited tumor cell invasion, intravasation, and metastasis. Haplodeficiency of PHD2 redirected the specification of endothelial tip cells to a more quiescent cell type, lacking filopodia and arrayed in a phalanx formation. This transition relied on HIF-driven upregulation of (soluble) VEGFR-1 and VE-cadherin. Thus, decreased activity of an oxygen sensor in hypoxic conditions prompts endothelial cells to readjust their shape and phenotype to restore oxygen supply. Inhibition of PHD2 may offer alternative therapeutic opportunities for anticancer therapy.
authors.affiliation: Vesalius Research Center, VIB-Vlaams Instituut voor Biotechnologie, 3000 Leuven, Belgium.|Vesalius Research Center, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Mazzone
authors.affiliation: Vesalius Research Center, VIB-Vlaams Instituut voor Biotechnologie, 3000 Leuven, Belgium.|Vesalius Research Center, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.|Laboratory of Cancer Genetics, Institute for Cancer Research and Treatment, University of Turin Medical School, 10060 Candiolo, Turin, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Dettori
authors.affiliation: Vesalius Research Center, VIB-Vlaams Instituut voor Biotechnologie, 3000 Leuven, Belgium.|Vesalius Research Center, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
authors.forename: Rodrigo Leite
authors.initials: RL
authors.lastname: de Oliveira
authors.affiliation: Vesalius Research Center, VIB-Vlaams Instituut voor Biotechnologie, 3000 Leuven, Belgium.|Vesalius Research Center, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
authors.forename: Sonja
authors.initials: S
authors.lastname: Loges
authors.affiliation: Vesalius Research Center, VIB-Vlaams Instituut voor Biotechnologie, 3000 Leuven, Belgium.|Vesalius Research Center, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
authors.forename: Thomas
authors.initials: T
authors.lastname: Schmidt
authors.affiliation: Vesalius Research Center, VIB-Vlaams Instituut voor Biotechnologie, 3000 Leuven, Belgium.|Vesalius Research Center, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
authors.forename: Bart
authors.initials: B
authors.lastname: Jonckx
authors.affiliation: The Henry Wellcome Building of Genomic Medicine, Oxford OX3 7BN, UK.
authors.forename: Ya-Min
authors.initials: YM
authors.lastname: Tian
authors.affiliation: Cardiovascular Medicine, Yale University, New Haven, CT 06510, USA.
authors.forename: Anthony A
authors.initials: AA
authors.lastname: Lanahan
authors.affiliation: The Henry Wellcome Building of Genomic Medicine, Oxford OX3 7BN, UK.
authors.forename: Patrick
authors.initials: P
authors.lastname: Pollard
authors.affiliation: Vesalius Research Center, VIB-Vlaams Instituut voor Biotechnologie, 3000 Leuven, Belgium.|Vesalius Research Center, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
authors.forename: Carmen Ruiz
authors.initials: CR
authors.lastname: de Almodovar
authors.affiliation: Vesalius Research Center, VIB-Vlaams Instituut voor Biotechnologie, 3000 Leuven, Belgium.|Vesalius Research Center, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
authors.forename: Frederik
authors.initials: F
authors.lastname: De Smet
authors.affiliation: Vesalius Research Center, VIB-Vlaams Instituut voor Biotechnologie, 3000 Leuven, Belgium.|Vesalius Research Center, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
authors.forename: Stefan
authors.initials: S
authors.lastname: Vinckier
authors.affiliation: Vesalius Research Center, VIB-Vlaams Instituut voor Biotechnologie, 3000 Leuven, Belgium.|Vesalius Research Center, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
authors.forename: Julián
authors.initials: J
authors.lastname: Aragonés
authors.affiliation: Vesalius Research Center, VIB-Vlaams Instituut voor Biotechnologie, 3000 Leuven, Belgium.|Vesalius Research Center, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
authors.forename: Koen
authors.initials: K
authors.lastname: Debackere
authors.affiliation: Center for Molecular and Vascular Biology, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
authors.forename: Aernout
authors.initials: A
authors.lastname: Luttun
authors.affiliation: Vesalius Research Center, VIB-Vlaams Instituut voor Biotechnologie, 3000 Leuven, Belgium.|Vesalius Research Center, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
authors.forename: Sabine
authors.initials: S
authors.lastname: Wyns
authors.affiliation: Biomedical Magnetic Resonance Unit, Medicinal Chemistry and Radiopharmacy U.C. Louvain, 1000 Brussels, Belgium.
authors.forename: Benedicte
authors.initials: B
authors.lastname: Jordan
authors.affiliation: Unit of Pathological Anatomy, Institute for Cancer Research and Treatment, 10060 Candiolo, Turin, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Pisacane
authors.affiliation: Biomedical Magnetic Resonance Unit, Medicinal Chemistry and Radiopharmacy U.C. Louvain, 1000 Brussels, Belgium.
authors.forename: Bernard
authors.initials: B
authors.lastname: Gallez
authors.affiliation: Vascular Biology Unit, Italian Foundation for Cancer Research Institute of Molecular Oncology, 20139 Milan, Italy.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Lampugnani
authors.affiliation: Vascular Biology Unit, Italian Foundation for Cancer Research Institute of Molecular Oncology, 20139 Milan, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Dejana
authors.affiliation: Cardiovascular Medicine, Yale University, New Haven, CT 06510, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Simons
authors.affiliation: The Henry Wellcome Building of Genomic Medicine, Oxford OX3 7BN, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Ratcliffe
authors.affiliation: Rayne Institute, University College London, London WC1E 6JJ, UK.
authors.forename: Patrick
authors.initials: P
authors.lastname: Maxwell
authors.affiliation: Vesalius Research Center, VIB-Vlaams Instituut voor Biotechnologie, 3000 Leuven, Belgium.|Vesalius Research Center, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000166:cytology* / Q000196:embryology / Q000378:metabolism; D048430:Cell Shape; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D006019:Glycolysis; D006579:Heterozygote; D000860:Hypoxia / Q000378:metabolism; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000098:blood supply* / Q000473:pathology; D010100:Oxygen / Q000378:metabolism*; D011393:Procollagen-Proline Dioxygenase
chemical_list: D004268:DNA-Binding Proteins; D017874:Immediate-Early Proteins; D011393:Procollagen-Proline Dioxygenase; C490189:Egln1 protein, mouse; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D010100:Oxygen