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 Lampugnani; Elisabetta Dejana; Michael Simons; Peter Ratcliffe; Patrick Maxwell; Peter Carmeliet

doi:10.1016/j.cell.2009.01.020

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

Istituto Oncologico Candiolo

Research output: Contribution to journal › Article › peer-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 language	English
Pages (from-to)	839-851
Number of pages	13
Journal	Cell
Volume	136
Issue number	5
DOIs	https://doi.org/10.1016/j.cell.2009.01.020
Publication status	Published - Mar 6 2009

Keywords

CELLBIO
HUMDISEASE

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

Access to Document

10.1016/j.cell.2009.01.020

Fingerprint Dive into the research topics of 'Heterozygous Deficiency of PHD2 Restores Tumor Oxygenation and Inhibits Metastasis via Endothelial Normalization'. Together they form a unique fingerprint.

Cite this

Mazzone, M., Dettori, D., Leite de Oliveira, R., Loges, S., Schmidt, T., Jonckx, B., Tian, Y. M., Lanahan, A. A., 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., ... Carmeliet, P. (2009). Heterozygous Deficiency of PHD2 Restores Tumor Oxygenation and Inhibits Metastasis via Endothelial Normalization. Cell, 136(5), 839-851. https://doi.org/10.1016/j.cell.2009.01.020

Heterozygous Deficiency of PHD2 Restores Tumor Oxygenation and Inhibits Metastasis via Endothelial Normalization. / Mazzone, Massimiliano; Dettori, Daniela; Leite de Oliveira, Rodrigo; Loges, Sonja; Schmidt, Thomas; Jonckx, Bart; Tian, Ya Min; Lanahan, Anthony A.; Pollard, Patrick; Ruiz de Almodovar, Carmen; De Smet, Frederik; Vinckier, Stefan; Aragonés, Julián; Debackere, Koen; Luttun, Aernout; Wyns, Sabine; Jordan, Benedicte; Pisacane, Alberto; Gallez, Bernard; Lampugnani, Maria Grazia; Dejana, Elisabetta; Simons, Michael; Ratcliffe, Peter; Maxwell, Patrick; Carmeliet, Peter.

In: Cell, Vol. 136, No. 5, 06.03.2009, p. 839-851.

Research output: Contribution to journal › Article › peer-review

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 2009, 'Heterozygous Deficiency of PHD2 Restores Tumor Oxygenation and Inhibits Metastasis via Endothelial Normalization', Cell, vol. 136, no. 5, pp. 839-851. https://doi.org/10.1016/j.cell.2009.01.020

Mazzone, Massimiliano ; Dettori, Daniela ; Leite de Oliveira, Rodrigo ; Loges, Sonja ; Schmidt, Thomas ; Jonckx, Bart ; Tian, Ya Min ; Lanahan, Anthony A. ; Pollard, Patrick ; Ruiz de Almodovar, Carmen ; De Smet, Frederik ; Vinckier, Stefan ; Aragonés, Julián ; Debackere, Koen ; Luttun, Aernout ; Wyns, Sabine ; Jordan, Benedicte ; Pisacane, Alberto ; Gallez, Bernard ; Lampugnani, Maria Grazia ; Dejana, Elisabetta ; Simons, Michael ; Ratcliffe, Peter ; Maxwell, Patrick ; Carmeliet, Peter. / Heterozygous Deficiency of PHD2 Restores Tumor Oxygenation and Inhibits Metastasis via Endothelial Normalization. In: Cell. 2009 ; Vol. 136, No. 5. pp. 839-851.

@article{5208a14dd12b42ef846c5018465fe596,

title = "Heterozygous Deficiency of PHD2 Restores Tumor Oxygenation and Inhibits Metastasis via Endothelial Normalization",

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.",

keywords = "CELLBIO, HUMDISEASE",

author = "Massimiliano Mazzone and Daniela Dettori and {Leite de Oliveira}, Rodrigo and Sonja Loges and Thomas Schmidt and Bart Jonckx and Tian, {Ya Min} and Lanahan, {Anthony A.} and Patrick Pollard and {Ruiz de Almodovar}, Carmen and {De Smet}, Frederik and Stefan Vinckier and Juli{\'a}n Aragon{\'e}s and Koen Debackere and Aernout Luttun and Sabine Wyns and Benedicte Jordan and Alberto Pisacane and Bernard Gallez and Lampugnani, {Maria Grazia} and Elisabetta Dejana and Michael Simons and Peter Ratcliffe and Patrick Maxwell and Peter Carmeliet",

year = "2009",

month = mar,

day = "6",

doi = "10.1016/j.cell.2009.01.020",

language = "English",

volume = "136",

pages = "839--851",

journal = "Cell",

issn = "0092-8674",

publisher = "Cell Press",

number = "5",

}

TY - JOUR

T1 - Heterozygous Deficiency of PHD2 Restores Tumor Oxygenation and Inhibits Metastasis via Endothelial Normalization

AU - Mazzone, Massimiliano

AU - Dettori, Daniela

AU - Leite de Oliveira, Rodrigo

AU - Loges, Sonja

AU - Schmidt, Thomas

AU - Jonckx, Bart

AU - Tian, Ya Min

AU - Lanahan, Anthony A.

AU - Pollard, Patrick

AU - Ruiz de Almodovar, Carmen

AU - De Smet, Frederik

AU - Vinckier, Stefan

AU - Aragonés, Julián

AU - Debackere, Koen

AU - Luttun, Aernout

AU - Wyns, Sabine

AU - Jordan, Benedicte

AU - Pisacane, Alberto

AU - Gallez, Bernard

AU - Lampugnani, Maria Grazia

AU - Dejana, Elisabetta

AU - Simons, Michael

AU - Ratcliffe, Peter

AU - Maxwell, Patrick

AU - Carmeliet, Peter

PY - 2009/3/6

Y1 - 2009/3/6

N2 - 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.

AB - 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.

KW - CELLBIO

KW - HUMDISEASE

UR - http://www.scopus.com/inward/record.url?scp=59649117924&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=59649117924&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2009.01.020

DO - 10.1016/j.cell.2009.01.020

M3 - Article

C2 - 19217150

AN - SCOPUS:59649117924

VL - 136

SP - 839

EP - 851

JO - Cell

JF - Cell

SN - 0092-8674

IS - 5

ER -