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

@article{Mazzone2009HeterozygousDO,
  title={Heterozygous Deficiency of PHD2 Restores Tumor Oxygenation and Inhibits Metastasis via Endothelial Normalization},
  author={M. Mazzone and D. Dettori and Rodrigo Leite de Oliveira and S. Loges and T. Schmidt and B. Jonckx and Ya-Min Tian and A. Lanahan and P. Pollard and C. Almod{\'o}var and F. Smet and S. Vinckier and J. Aragon{\'e}s and K. Debackere and A. Luttun and S. Wyns and B. Jordan and A. Pisacane and B. Gallez and M. Lampugnani and E. Dejana and M. Simons and P. Ratcliffe and P. Maxwell and P. Carmeliet},
  journal={Cell},
  year={2009},
  volume={136},
  pages={839-851}
}
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… Expand
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References

SHOWING 1-10 OF 64 REFERENCES
Hypoxia-driven selection of the metastatic phenotype
TLDR
Through regulation of these critical molecular targets, hypoxia promotes each step of the metastatic cascade and selects tumor cell populations that are able to escape the unfavorable microenvironment of the primary tumor. Expand
The Biphasic Role of the Hypoxia-Inducible Factor Prolyl-4-Hydroxylase, PHD2, in Modulating Tumor-Forming Potential
TLDR
It is found that overexpression of PHD2 in malignant fibroblasts leads to loss of the tumorigenic phenotype, and these findings support a biphasic model for the relationship betweenPHD2 activity and malignant transformation. Expand
Vascular normalization in Rgs5-deficient tumours promotes immune destruction
TLDR
This is the first demonstration, to the authors' knowledge, of reduced tumour angiogenesis and improved immune therapeutic outcome on loss of a vascular gene function and establishes a previously unrecognized role of G-protein signalling in tumourAngiogenesis. Expand
Deletion of Vascular Endothelial Growth Factor in myeloid cells accelerates tumorigenesis
TLDR
Deletion of myeloid-cell VEGF-A resulted in an accelerated tumour progression in multiple subcutaneous isograft models and an autochthonous transgenic model of mammary tumorigenesis, with less overall tumour cell death and decreased tumour hypoxia. Expand
Hypoxia-inducible Transcription Factor-2α in Endothelial Cells Regulates Tumor Neovascularization through Activation of Ephrin A1*
TLDR
It is concluded that in ECs, HIF-2α plays an essential role in vascular remodeling during tumor vascularization through activation of at least ephrin A1. Expand
Essential Role for Prolyl Hydroxylase Domain Protein 2 in Oxygen Homeostasis of the Adult Vascular System
TLDR
PHD2, but not PHD1 and PHD3, is a major negative regulator for vascular growth in adult mice, and increased angiogenesis in PHD2-deficient mice may be mediated by a novel systemic mechanism. Expand
Robo4 stabilizes the vascular network by inhibiting pathologic angiogenesis and endothelial hyperpermeability.
TLDR
A previously unknown function for Robo receptors in stabilizing the vasculature is defined and it is suggested that activating Robo4 may have broad therapeutic application in diseases characterized by excessive angiogenesis and/or vascular leak. Expand
Cellular abnormalities of blood vessels as targets in cancer.
TLDR
Rapid vascular regrowth reflects the ongoing drive for angiogenesis and bizarre microenvironment in tumors that promote vascular abnormalities and thereby create therapeutic targets. Expand
Overexpression of the Oxygen Sensors PHD-1, PHD-2, PHD-3, and FIH Is Associated with Tumor Aggressiveness in Pancreatic Endocrine Tumors
TLDR
HIF regulatory proteins are highly expressed in PET and their expression is correlated with tumor metastases, tumor recurrence, and prognosis, and these molecules that play an important role in the control of hypoxia-induced genes may have a function in the regulation of cellular proliferation and differentiation during endocrine tumorigenesis. Expand
Enhancement of angiogenesis through stabilization of hypoxia-inducible factor-1 by silencing prolyl hydroxylase domain-2 gene.
TLDR
It is shown that the specific silencing of PHD2 is sufficient for stabilizing HIF-1alpha and increasing its transcriptional activity, resulting in the increased expression of angiogenic factors including VEGF and fibroblast growth factor-2 (FGF2). Expand
...
1
2
3
4
5
...