| Literature DB >> 19217150 |
Massimiliano Mazzone1,2, Daniela Dettori1,2,3, Rodrigo Leite de Oliveira1,2, Sonja Loges1,2, Thomas Schmidt1,2, Bart Jonckx1,2, Ya-Min Tian4, Anthony A Lanahan5, Patrick Pollard4, Carmen Ruiz de Almodovar1,2, Frederik De Smet1,2, Stefan Vinckier1,2, Julián Aragonés1,2, Koen Debackere1,2, Aernout Luttun6, Sabine Wyns1,2, Benedicte Jordan7, Alberto Pisacane8, Bernard Gallez7, Maria Grazia Lampugnani9, Elisabetta Dejana9, Michael Simons5, Peter Ratcliffe4, Patrick Maxwell10, Peter Carmeliet1,2.
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.Entities:
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Year: 2009 PMID： 19217150 PMCID： PMC4037868 DOI： 10.1016/j.cell.2009.01.020
Source DB: PubMed Journal: Cell ISSN： 0092-8674 Impact factor: 41.582