Title: Heterozygous Deficiency of PHD2 Restores Tumor Oxygenation and Inhibits Metastasis via Endothelial Normalization
Authors: Mazzone, Massimiliano
Dettori, Daniela
Leite-de-Oliveira, Rodrigo
Loges, Sonja
Schmidt, Thomas
Jonckx, Bart
Tian, Ya-Min
Lanahan, Anthony A
Pollard, Patrick
Ruiz de Almodovar Egea, Carmen
De Smet, Frederik
Vinckier, Stefan
Aragones, Julian
Debackere, Koen
Luttun, Aernout
Wyns, Sabine
Jordan, Benedicte
Pisacane, Alberto
Gallez, Bernard
Lampugnani, Maria Grazia
Dejana, Elisabetta
Simons, Michael
Ratcliffe, Peter
Maxwell, Patrick
Carmeliet, Peter # ×
Issue Date: Mar-2009
Publisher: Cell press
Series Title: Cell vol:136 issue:5 pages:839-851
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.
ISSN: 0092-8674
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Vesalius Research Centre (-)
Molecular and Vascular Biology
Switch Laboratory
Laboratory of Tumor Inflammation and Angiogenesis (Vesalius Research Center) (+)
Laboratory of Angiogenesis and Vascular Metabolism (Vesalius Research Center) (+)
× corresponding author
# (joint) last author

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