1: Cell. 2009 Mar 6;136(5):839-51. Epub 2009 Feb 12.

Comment in:
    Cell. 2009 Mar 6;136(5):810-2.

Heterozygous deficiency of PHD2 restores tumor oxygenation and inhibits
metastasis via endothelial normalization.

Mazzone M, Dettori D, Leite de Oliveira R, Loges S, Schmidt T, Jonckx B, Tian YM,
Lanahan AA, Pollard P, Ruiz de Almodovar C, De Smet F, Vinckier S, Aragonés J,
Debackere K, Luttun A, Wyns S, Jordan B, Pisacane A, Gallez B, Lampugnani MG,
Dejana E, Simons M, Ratcliffe P, Maxwell P, Carmeliet P.

Vesalius Research Center, VIB-Vlaams Instituut voor Biotechnologie, Leuven,
Belgium.

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.


PMID: 19217150 [PubMed - in process]

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