Heterozygous deficiency of PHD2 restores tumor oxygenation and inhibits metastasis via endothelial normalization.
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Heterozygous deficiency of PHD2 restores tumor oxygenation and inhibits metastasis via endothelial normalization. / Mazzone, Massimiliano; Dettori, Daniela; Rodrigo, Leite de Oliveira; Loges, Sonja; Schmidt, Thomas; Jonckx, Bart; Tian, Ya-Min; Lanahan, Anthony A; Pollard, Patrick; Carmen, Ruiz de Almodovar; Frederik, De Smet; Vinckier, Stefan; Aragonés, Julián; 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.
in: CELL, Jahrgang 136, Nr. 5, 5, 2009, S. 839-851.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - Heterozygous deficiency of PHD2 restores tumor oxygenation and inhibits metastasis via endothelial normalization.
AU - Mazzone, Massimiliano
AU - Dettori, Daniela
AU - Rodrigo, Leite de Oliveira
AU - Loges, Sonja
AU - Schmidt, Thomas
AU - Jonckx, Bart
AU - Tian, Ya-Min
AU - Lanahan, Anthony A
AU - Pollard, Patrick
AU - Carmen, Ruiz de Almodovar
AU - Frederik, De Smet
AU - Vinckier, Stefan
AU - Aragonés, Julián
AU - Debackere, Koen
AU - Luttun, Aernout
AU - Wyns, Sabine
AU - Jordan, Benedicte
AU - Pisacane, Alberto
AU - Gallez, Bernard
AU - Lampugnani, Maria Grazia
AU - Dejana, Elisabetta
AU - Simons, Michael
AU - Ratcliffe, Peter
AU - Maxwell, Patrick
AU - Carmeliet, Peter
PY - 2009
Y1 - 2009
N2 - 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.
AB - 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.
M3 - SCORING: Zeitschriftenaufsatz
VL - 136
SP - 839
EP - 851
JO - CELL
JF - CELL
SN - 0092-8674
IS - 5
M1 - 5
ER -