Heterozygous deficiency of PHD2 restores tumor oxygenation and inhibits metastasis via endothelial normalization.
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(+/-)...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
2009
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| _version_ | 1797066823822213120 |
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| author | Mazzone, M Dettori, D Leite de Oliveira, R Loges, S Schmidt, T Jonckx, B Tian, Y Lanahan, 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 Lampugnani, MG Dejana, E Simons, M Ratcliffe, P Maxwell, P Carmeliet, P |
| author_facet | Mazzone, M Dettori, D Leite de Oliveira, R Loges, S Schmidt, T Jonckx, B Tian, Y Lanahan, 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 Lampugnani, MG Dejana, E Simons, M Ratcliffe, P Maxwell, P Carmeliet, P |
| author_sort | Mazzone, M |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-06T21:47:31Z |
| format | Journal article |
| id | oxford-uuid:4a1bc6fd-8bc8-4f4f-9418-7e21eba64f8e |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T21:47:31Z |
| publishDate | 2009 |
| record_format | dspace |
| spelling | oxford-uuid:4a1bc6fd-8bc8-4f4f-9418-7e21eba64f8e2022-03-26T15:35:44ZHeterozygous deficiency of PHD2 restores tumor oxygenation and inhibits metastasis via endothelial normalization.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:4a1bc6fd-8bc8-4f4f-9418-7e21eba64f8eEnglishSymplectic Elements at Oxford2009Mazzone, MDettori, DLeite de Oliveira, RLoges, SSchmidt, TJonckx, BTian, YLanahan, APollard, PRuiz de Almodovar, CDe Smet, FVinckier, SAragonés, JDebackere, KLuttun, AWyns, SJordan, BPisacane, AGallez, BLampugnani, MGDejana, ESimons, MRatcliffe, PMaxwell, PCarmeliet, PA 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. |
| spellingShingle | Mazzone, M Dettori, D Leite de Oliveira, R Loges, S Schmidt, T Jonckx, B Tian, Y Lanahan, 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 Lampugnani, MG Dejana, E Simons, M Ratcliffe, P Maxwell, P Carmeliet, P Heterozygous deficiency of PHD2 restores tumor oxygenation and inhibits metastasis via endothelial normalization. |
| title | Heterozygous deficiency of PHD2 restores tumor oxygenation and inhibits metastasis via endothelial normalization. |
| title_full | Heterozygous deficiency of PHD2 restores tumor oxygenation and inhibits metastasis via endothelial normalization. |
| title_fullStr | Heterozygous deficiency of PHD2 restores tumor oxygenation and inhibits metastasis via endothelial normalization. |
| title_full_unstemmed | Heterozygous deficiency of PHD2 restores tumor oxygenation and inhibits metastasis via endothelial normalization. |
| title_short | Heterozygous deficiency of PHD2 restores tumor oxygenation and inhibits metastasis via endothelial normalization. |
| title_sort | heterozygous deficiency of phd2 restores tumor oxygenation and inhibits metastasis via endothelial normalization |
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