Heterozygous deficiency of PHD2 restores tumor oxygenation and inhibits metastasis via endothelial normalization.
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.
Mazzone
Massimiliano
M
Vesalius Research Center, VIB-Vlaams Instituut voor Biotechnologie, 3000 Leuven, Belgium.|Vesalius Research Center, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
Dettori
Daniela
D
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.
de Oliveira
Rodrigo Leite
RL
Vesalius Research Center, VIB-Vlaams Instituut voor Biotechnologie, 3000 Leuven, Belgium.|Vesalius Research Center, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
Loges
Sonja
S
Vesalius Research Center, VIB-Vlaams Instituut voor Biotechnologie, 3000 Leuven, Belgium.|Vesalius Research Center, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
Schmidt
Thomas
T
Vesalius Research Center, VIB-Vlaams Instituut voor Biotechnologie, 3000 Leuven, Belgium.|Vesalius Research Center, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
Jonckx
Bart
B
Vesalius Research Center, VIB-Vlaams Instituut voor Biotechnologie, 3000 Leuven, Belgium.|Vesalius Research Center, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
Tian
Ya-Min
YM
The Henry Wellcome Building of Genomic Medicine, Oxford OX3 7BN, UK.
Lanahan
Anthony A
AA
Cardiovascular Medicine, Yale University, New Haven, CT 06510, USA.
Pollard
Patrick
P
The Henry Wellcome Building of Genomic Medicine, Oxford OX3 7BN, UK.
de Almodovar
Carmen Ruiz
CR
Vesalius Research Center, VIB-Vlaams Instituut voor Biotechnologie, 3000 Leuven, Belgium.|Vesalius Research Center, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
De Smet
Frederik
F
Vesalius Research Center, VIB-Vlaams Instituut voor Biotechnologie, 3000 Leuven, Belgium.|Vesalius Research Center, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
Vinckier
Stefan
S
Vesalius Research Center, VIB-Vlaams Instituut voor Biotechnologie, 3000 Leuven, Belgium.|Vesalius Research Center, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
Aragonés
Julián
J
Vesalius Research Center, VIB-Vlaams Instituut voor Biotechnologie, 3000 Leuven, Belgium.|Vesalius Research Center, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
Debackere
Koen
K
Vesalius Research Center, VIB-Vlaams Instituut voor Biotechnologie, 3000 Leuven, Belgium.|Vesalius Research Center, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
Luttun
Aernout
A
Center for Molecular and Vascular Biology, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
Wyns
Sabine
S
Vesalius Research Center, VIB-Vlaams Instituut voor Biotechnologie, 3000 Leuven, Belgium.|Vesalius Research Center, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
Jordan
Benedicte
B
Biomedical Magnetic Resonance Unit, Medicinal Chemistry and Radiopharmacy U.C. Louvain, 1000 Brussels, Belgium.
Pisacane
Alberto
A
Unit of Pathological Anatomy, Institute for Cancer Research and Treatment, 10060 Candiolo, Turin, Italy.
Gallez
Bernard
B
Biomedical Magnetic Resonance Unit, Medicinal Chemistry and Radiopharmacy U.C. Louvain, 1000 Brussels, Belgium.
Lampugnani
Maria Grazia
MG
Vascular Biology Unit, Italian Foundation for Cancer Research Institute of Molecular Oncology, 20139 Milan, Italy.
Dejana
Elisabetta
E
Vascular Biology Unit, Italian Foundation for Cancer Research Institute of Molecular Oncology, 20139 Milan, Italy.
Simons
Michael
M
Cardiovascular Medicine, Yale University, New Haven, CT 06510, USA.
Ratcliffe
Peter
P
The Henry Wellcome Building of Genomic Medicine, Oxford OX3 7BN, UK.
Maxwell
Patrick
P
Rayne Institute, University College London, London WC1E 6JJ, UK.
Carmeliet
Peter
P
Vesalius Research Center, VIB-Vlaams Instituut voor Biotechnologie, 3000 Leuven, Belgium.|Vesalius Research Center, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
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
D004268:DNA-Binding Proteins; D017874:Immediate-Early Proteins; D011393:Procollagen-Proline Dioxygenase; C490189:Egln1 protein, mouse; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D010100:Oxygen