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PMID: 19217150 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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

Cell ·Vol. 136 ·No. 5 ·2009-03-06 ·Pages 839-851

Mazzone M, Dettori D, de Oliveira RL, Loges S, Schmidt T, Jonckx B, Tian YM, Lanahan AA, Pollard P, de Almodovar CR, 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

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.

MeSH Terms
Animals Blood Vessels/cytology,embryology,metabolism Cell Shape DNA-Binding Proteins/genetics,metabolism Endothelial Cells/cytology,metabolism Glycolysis Heterozygote Hypoxia/metabolism Hypoxia-Inducible Factor-Proline Dioxygenases Immediate-Early Proteins/genetics,metabolism Mice Neoplasm Metastasis Neoplasms/blood supply,pathology Oxygen/metabolism Procollagen-Proline Dioxygenase
Chemicals
DNA-Binding Proteins Immediate-Early Proteins Procollagen-Proline Dioxygenase Egln1 protein, mouse Hypoxia-Inducible Factor-Proline Dioxygenases Oxygen
Authors & Affiliations
25 authors, click to expand affiliations / ORCID
Mazzone Massimiliano
Vesalius Research Center, VIB-Vlaams Instituut voor Biotechnologie, 3000 Leuven, Belgium. | Vesalius Research Center, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
Dettori Daniela
Vesalius Research Center, VIB-Vlaams Instituut voor Biotechnologie, 3000 Leuven, Belgium. | Vesalius Research Center, Katholieke Universiteit Leuven, 3000 Leuven, Belgium. | Laboratory of Cancer Genetics, Institute for Cancer Research and Treatment, University of Turin Medical School, 10060 Candiolo, Turin, Italy.
de Oliveira Rodrigo Leite
Vesalius Research Center, VIB-Vlaams Instituut voor Biotechnologie, 3000 Leuven, Belgium. | Vesalius Research Center, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
Loges Sonja
Vesalius Research Center, VIB-Vlaams Instituut voor Biotechnologie, 3000 Leuven, Belgium. | Vesalius Research Center, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
Schmidt Thomas
Vesalius Research Center, VIB-Vlaams Instituut voor Biotechnologie, 3000 Leuven, Belgium. | Vesalius Research Center, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
Jonckx Bart
Vesalius Research Center, VIB-Vlaams Instituut voor Biotechnologie, 3000 Leuven, Belgium. | Vesalius Research Center, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
Tian Ya-Min
The Henry Wellcome Building of Genomic Medicine, Oxford OX3 7BN, UK.
Lanahan Anthony A
Cardiovascular Medicine, Yale University, New Haven, CT 06510, USA.
Pollard Patrick
The Henry Wellcome Building of Genomic Medicine, Oxford OX3 7BN, UK.
de Almodovar Carmen Ruiz
Vesalius Research Center, VIB-Vlaams Instituut voor Biotechnologie, 3000 Leuven, Belgium. | Vesalius Research Center, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
De Smet Frederik
Vesalius Research Center, VIB-Vlaams Instituut voor Biotechnologie, 3000 Leuven, Belgium. | Vesalius Research Center, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
Vinckier Stefan
Vesalius Research Center, VIB-Vlaams Instituut voor Biotechnologie, 3000 Leuven, Belgium. | Vesalius Research Center, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
Aragonés Julián
Vesalius Research Center, VIB-Vlaams Instituut voor Biotechnologie, 3000 Leuven, Belgium. | Vesalius Research Center, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
Debackere Koen
Vesalius Research Center, VIB-Vlaams Instituut voor Biotechnologie, 3000 Leuven, Belgium. | Vesalius Research Center, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
Luttun Aernout
Center for Molecular and Vascular Biology, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
Wyns Sabine
Vesalius Research Center, VIB-Vlaams Instituut voor Biotechnologie, 3000 Leuven, Belgium. | Vesalius Research Center, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
Jordan Benedicte
Biomedical Magnetic Resonance Unit, Medicinal Chemistry and Radiopharmacy U.C. Louvain, 1000 Brussels, Belgium.
Pisacane Alberto
Unit of Pathological Anatomy, Institute for Cancer Research and Treatment, 10060 Candiolo, Turin, Italy.
Gallez Bernard
Biomedical Magnetic Resonance Unit, Medicinal Chemistry and Radiopharmacy U.C. Louvain, 1000 Brussels, Belgium.
Lampugnani Maria Grazia
Vascular Biology Unit, Italian Foundation for Cancer Research Institute of Molecular Oncology, 20139 Milan, Italy.
Dejana Elisabetta
Vascular Biology Unit, Italian Foundation for Cancer Research Institute of Molecular Oncology, 20139 Milan, Italy.
Simons Michael
Cardiovascular Medicine, Yale University, New Haven, CT 06510, USA.
Ratcliffe Peter
The Henry Wellcome Building of Genomic Medicine, Oxford OX3 7BN, UK.
Maxwell Patrick
Rayne Institute, University College London, London WC1E 6JJ, UK.
Carmeliet Peter
Vesalius Research Center, VIB-Vlaams Instituut voor Biotechnologie, 3000 Leuven, Belgium. | Vesalius Research Center, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
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Article Info
Journal
Cell
Abbr.
Cell
ISSN
1097-4172
DOI
10.1016/j.cell.2009.01.020
Published
2009-03-06
Epub
2009-00-12
Pages
839-851
Language
English
Region
United States
NLM ID
0413066
PMCID
PMC4037868
Subset
IM
Grants
NHLBI NIH HHS · R01 HL053793 · United States
Corrections
CommentIn
PMID: 19269358
CommentIn
PMID: 27533033
External Links
PubMed source DOI: 10.1016/j.cell.2009.01.020 PMC Full Text View journal details
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