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

Massimiliano Mazzone, Daniela Dettori, Rodrigo Leite de Oliveira, Sonja Loges, Thomas Schmidt, Bart Jonckx, Ya Min Tian, Anthony A. Lanahan, Patrick Pollard, Carmen Ruiz de Almodovar, Frederik De Smet, Stefan Vinckier, Julián Aragonés, Koen Debackere, Aernout Luttun, Sabine Wyns, Benedicte Jordan, Alberto Pisacane, Bernard Gallez, Maria Grazia LampugnaniElisabetta Dejana, Michael Simons, Peter Ratcliffe, Patrick Maxwell, Peter Carmeliet

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)839-851
Number of pages13
JournalCell
Volume136
Issue number5
DOIs
Publication statusPublished - Mar 6 2009

Keywords

  • CELLBIO
  • HUMDISEASE

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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