Heterozygous Deficiency of PHD2 Restores Tumor Oxygenation and Inhibits Metastasis via Endothelial Normalization

被引：640

作者：

Mazzone, Massimiliano ^{[1
,2
]}

Dettori, Daniela ^{[1
,2
,3
]}

de Oliveira, Rodrigo Leite ^{[1
,2
]}

Loges, Sonja ^{[1
,2
]}

Schmidt, Thomas ^{[1
,2
]}

Jonckx, Bart ^{[1
,2
]}

Tian, Ya-Min ^{[4
]}

Lanahan, Anthony A. ^{[5
]}

Pollard, Patrick ^{[4
]}

de Almodovar, Carmen Ruiz ^{[1
,2
]}

De Smet, Frederik ^{[1
,2
]}

Vinckier, Stefan ^{[1
,2
]}

Aragones, Julian ^{[1
,2
]}

Debackere, Koen ^{[1
,2
]}

Luttun, Aemout ^{[6
]}

Wyns, Sabine ^{[1
,2
]}

Jordan, Benedicte ^{[7
]}

Pisacane, Alberto ^{[8
]}

Gallez, Bernard ^{[7
]}

Lampugnani, Maria Grazia ^{[9
]}

Dejana, Elisabetta ^{[9
]}

Simons, Michael

Ratcliffe, Peter ^{[4
]}

Maxwell, Patrick ^{[10
]}

Carmeliet, Peter ^{[1
,2
]}

机构：

[1] VIB Vlaams Inst Biotechnol, Vesalius Res Ctr, B-3000 Louvain, Belgium

[2] Katholieke Univ Leuven, Vesalius Res Ctr, B-3000 Louvain, Belgium

[3] Univ Turin, Sch Med, Canc Genet Lab, Inst Canc Res & Treatment, I-10060 Turin, Italy

[4] Henry Wellcome Bldg Genom Med, Oxford OX3 7BN, England

[5] Yale Univ, New Haven, CT 06510 USA

[6] Katholieke Univ Leuven, Ctr Mol & Vasc Biol, B-3000 Louvain, Belgium

[7] Med Chem & Radiopharm UC Louvain, Biomed Magnet Resonance Unit, B-1000 Brussels, Belgium

[8] Inst Canc Res & Treatment, Anat Pathol Unit, I-10060 Turin, Italy

[9] Italian Fdn Canc Res, Inst Mol Oncol, Vasc Biol Unit, I-20139 Milan, Italy

[10] UCL, Rayne Inst, London WC1E 6JJ, England

来源：

CELL | 2009年 / 136卷 / 05期

关键词：

INDUCIBLE FACTOR-I; VASCULAR NORMALIZATION; ANGIOGENESIS; VEGF; HYPOXIA; CADHERIN; CELLS; ACTIVATION; VESSELS; CANCER;

D O I：

10.1016/j.cell.2009.01.020

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：839 / 851

页数：13

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