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Cell. 2009 Mar 6;136(5):839-851. doi: 10.1016/j.cell.2009.01.020. Epub 2009 Feb 12.

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

Author information

1
Vesalius Research Center, VIB-Vlaams Instituut voor Biotechnologie, 3000 Leuven, Belgium.
2
Vesalius Research Center, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
3
Laboratory of Cancer Genetics, Institute for Cancer Research and Treatment, University of Turin Medical School, 10060 Candiolo, Turin, Italy.
4
The Henry Wellcome Building of Genomic Medicine, Oxford OX3 7BN, UK.
5
Cardiovascular Medicine, Yale University, New Haven, CT 06510, USA.
6
Center for Molecular and Vascular Biology, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
7
Biomedical Magnetic Resonance Unit, Medicinal Chemistry and Radiopharmacy U.C. Louvain, 1000 Brussels, Belgium.
8
Unit of Pathological Anatomy, Institute for Cancer Research and Treatment, 10060 Candiolo, Turin, Italy.
9
Vascular Biology Unit, Italian Foundation for Cancer Research Institute of Molecular Oncology, 20139 Milan, Italy.
10
Rayne Institute, University College London, London WC1E 6JJ, UK.
#
Contributed equally

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.

PMID:
19217150
PMCID:
PMC4037868
DOI:
10.1016/j.cell.2009.01.020
[Indexed for MEDLINE]
Free PMC Article

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