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

Mazzone, Massimiliano; Dettori, Daniela; Oliveira, Rodrigo Leite de; Loges, Sonja; Schmidt, Thomas; Jonckx, Bart; Tian, Ya-Min; Lanahan, Anthony A.; Pollard, Patrick J.; Almodóvar, Carmen Ruiz de; Smet, Frederik De; Vinckier, Stefan; Aragonés, Julián; Debackere, Koen; Luttun, Aernout; Wyns, Sabine; Jordan, Bénédicte F.; Pisacane, Alberto; Gallez, Bernard; Lampugnani, Maria Grazia; Dejana, Elisabetta; Simons, Michael; Ratcliffe, Peter J.; Maxwell, Patrick H.; Carmeliet, Peter

doi:10.1016/j.cell.2009.01.020

Cited by 725 publications

(748 citation statements)

References 41 publications

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“…Thereafter, sustained in vivo PHD2 suppression was confirmed on the mRNA as well as on the protein levels (Supplementary Figure S3). Recently, it has been proposed that heterozygous endothelial Phd2 deficiency stabilizes tumor vasculature and inhibits metastasis (Mazzone et al, 2009). Although tumors in our model were wild type for Phd2 in hostderived endothelial cells, we did not observe metastasis in mice subcutaneously injected with shPHD2 cells.…”

Section: Increased Tumor Progression By Phd2 Downregulationcontrasting

confidence: 68%

“…In tumor angiogenesis, PHD2 levels have to be considered not only in cancer cells but also in stromal cells. Indeed, endothelial PHD2 levels have been reported to dramatically affect tumor growth by influencing intratumoral vessel development (Mazzone et al, 2009). In summary, accumulating evidence suggests an important regulatory role of PHD2 in tumor angiogenesis.…”

Section: Discussionmentioning

confidence: 99%

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Prolyl-4-hydroxylase PHD2- and hypoxia-inducible factor 2-dependent regulation of amphiregulin contributes to breast tumorigenesis

et al. 2010

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Hypoxia-elicited adaptations of tumor cells are essential for tumor growth and cancer progression. Although ample evidence exists for a positive correlation between hypoxiainducible factors (HIFs) and tumor formation, metastasis and bad prognosis, the function of the HIF-a protein stability regulating prolyl-4-hydroxylase domain enzyme PHD2 in carcinogenesis is less well understood. In this study, we demonstrate that downregulation of PHD2 leads to increased tumor growth in a hormone-dependent mammary carcinoma mouse model. Tissue microarray analysis of PHD2 protein expression in 281 clinical samples of human breast cancer showed significantly shorter survival times of patients with low-level PHD2 tumors over a period of 10 years. An angiogenesis-related antibody array identified, amongst others, amphiregulin to be increased in the absence of PHD2 and normalized after PHD2 reconstitution. Cultivation of endothelial cells in conditioned media derived from PHD2-downregulated cells resulted in enhanced tube formation that was blocked by the addition of neutralizing anti-amphiregulin antibodies. Functionally, amphiregulin was regulated on the transcriptional level specifically by HIF-2 but not HIF-1. Our data suggest that PHD2/HIF-2/amphiregulin signaling has a critical role in the regulation of breast tumor progression and propose PHD2 as a potential tumor suppressor in breast cancer.

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Section: Increased Tumor Progression By Phd2 Downregulationcontrasting

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Prolyl-4-hydroxylase PHD2- and hypoxia-inducible factor 2-dependent regulation of amphiregulin contributes to breast tumorigenesis

et al. 2010

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“…In inflammatory bowel disease and chronic kidney failure, DMOG reduced secretion of proinflammatory cytokines, macrophage infiltration, and oxidative stress (48,49). Furthermore, in PHD2-haplodeficient mice, HIF-1 activity normalized blood vessel maturation and oxygen supply (50).…”

Section: Discussionmentioning

confidence: 99%

Hypoxia induces mitochondrial mutagenesis and dysfunction in inflammatory arthritis

Biniecka¹,

Fox²,

Gao³

et al. 2011

Arthritis & Rheumatism

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Objective. To assess the levels and spectrum of mitochondrial DNA (mtDNA) point mutations in synovial tissue from patients with inflammatory arthritis in relation to in vivo hypoxia and oxidative stress levels.Methods. Random Mutation Capture assay was used to quantitatively evaluate alterations of the synovial mitochondrial genome. In vivo tissue oxygen levels (tPO 2 ) were measured at arthroscopy using a Results. The median tPO 2 level in synovial tissue indicated significant hypoxia (25.47 mm Hg). Higher frequency of mtDNA mutations was associated with reduced in vivo oxygen tension (P ‫؍‬ 0.05) and with higher synovial 4-HNE cytoplasmic expression (P ‫؍‬ 0.04). Synovial expression of CytcO II correlated with in vivo tPO 2 levels (P ‫؍‬ 0.03), and levels were lower in patients with tPO 2 <20 mm Hg (P < 0.05). In vitro levels of mtDNA mutations, ROS, mitochondrial membrane potential, 8-oxo-dG, and 4-HNE were higher in synoviocytes exposed to 1% hypoxia (P < 0.05); all of these increased levels were rescued by SOD and DMOG and, with the exception of ROS, by NAC.Conclusion. These findings demonstrate that hypoxia-induced mitochondrial dysfunction drives mitochondrial genome mutagenesis, and antioxidants significantly rescue these events.

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“…Interestingly, in our experiments, it was associated with smaller infarcts and was specific to DMOG treatment. Recently, it has been shown that haplodeficiency of PHD-2, by upregulation of HIF-2 and VEGFR-1 and VE-cadherin, leads to improved tumor perfusion and oxygenation and inhibited tumor cell invasion, intravasation, and metastasis (Mazzone et al, 2009). We did neither measure HIF-2, VEGFR-1, nor VE-cadherin; hence, a role for these mediators in cerebral perfusion remains speculative, but VEGF was also significantly altered after tMCAO and DMOG treatment compared with controls.…”

Section: Discussionmentioning

confidence: 99%

Neuroprotection by Dimethyloxalylglycine following Permanent and Transient Focal Cerebral Ischemia in Rats

Nagel

Papadakis

Chen

et al. 2010

J Cereb Blood Flow Metab

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Dimethyloxalylglycine (DMOG) is an inhibitor of prolyl-4-hydroxylase domain (PHD) enzymes that regulate the stability of hypoxia-inducible factor (HIF). We investigated the effect of DMOG on the outcome after permanent and transient middle cerebral artery occlusion (p/tMCAO) in the rat. Before and after pMCAO, rats were treated with 40 mg/kg, 200 mg/kg DMOG, or vehicle, and with 40 mg/kg or vehicle after tMCAO. Serial magnetic resonance imaging (MRI) was performed to assess infarct evolution and regional cerebral blood flow (rCBF). Both doses significantly reduced infarct volumes, but only 40 mg/kg improved the behavior after 24 hours of pMCAO. Animals receiving 40 mg/kg were more likely to maintain rCBF values above 30% from the contralateral hemisphere within 24 hours of pMCAO. DMOG after tMCAO significantly reduced the infarct volumes and improved behavior at 24 hours and 8 days and also improved the rCBF after 24 hours. A consistent and significant upregulation of both mRNA and protein levels of vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS) was associated with the observed neuroprotection, although this was not consistently related to HIF-1a levels at 24 hours and 8 days. Thus, DMOG afforded neuroprotection both at 24 hours after pMCAO and at 24 hours and 8 days after tMCAO. This effect was associated with an increase of VEGF and eNOS and was mediated by improved rCBF after DMOG treatment.

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

Cited by 725 publications

References 41 publications

Prolyl-4-hydroxylase PHD2- and hypoxia-inducible factor 2-dependent regulation of amphiregulin contributes to breast tumorigenesis

Prolyl-4-hydroxylase PHD2- and hypoxia-inducible factor 2-dependent regulation of amphiregulin contributes to breast tumorigenesis

Hypoxia induces mitochondrial mutagenesis and dysfunction in inflammatory arthritis

Neuroprotection by Dimethyloxalylglycine following Permanent and Transient Focal Cerebral Ischemia in Rats

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