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

By M. Mazzone, Daniela Dettori, Rodrigo Leite de Oliveira, S. Loges, T. Schmidt, B. Jonckx, Ya-min Tian, A. Lanahan, Patrick J. Pollard, Carmen Ruiz de Almodóvar and 15 more. Cell, 2009

833 citations recorded by the source corpus.

SUMMARY 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.

Subfields: Cancer Research, Molecular Biology, Surgery

View Paper: https://www.semanticscholar.org/paper/b4e9d29806e45e5f966a63ea02c4f9035cb612d6

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Citations in the corpus

Tumor angiogenesis and vascular normalization: alternative therapeutic targets (2017, background): “Interestingly, after VEGF stimulation in Phd2 model, ECs showed reduced proliferation and displayed decreased motility and formation of lamellipodia compared to ECs in the wild-type model [48].”
Ischemia and reperfusion—from mechanism to translation (2011, background): “This effect can be mimicked pharmacologically by PHD inhibitors via its stabilizing effects on HIF”
Basic and therapeutic aspects of angiogenesis. (2011, positive): “function, so that improved perfusion and oxygenation counteract the hypoxia-driven expression of genes controlling epithelial-mesenchymal transition, invasion, and intravasation, which prompt the metastatic switch (Goel et al., 2011; Mazzone et al., 2009; Rolny et al., 2011) (Figure 7B).”
Delivering nanomedicine to solid tumors (2010, background): “In another example, haplodeficiency of the oxygen-sensing prolyl hydroxylase domain protein PHD2 normalized the endothelial lining resulting in reduced vessel leakiness and increased tumor perfusion and oxygenation”
HRG inhibits tumor growth and metastasis by inducing macrophage polarization and vessel normalization through downregulation of PlGF. (2011, methodology): “We thus focused on vessel normalization and antitumor immunity, known to regulate tumor growth and metastasis (Mantovani and Sica, 2010; Mazzone et al., 2009).”
Molecular mechanisms and clinical applications of angiogenesis (2011, background): “Notably, oxygen sensors control VE-cadherin expression in a feedback loop, so vessel perfusion can be optimized when the oxygen supply is insufficien”
Molecular control of endothelial cell behaviour during blood vessel morphogenesis (2011, background): “In stable vessels, ECs typically form a cobblestone-like monolayer of inactive cells that lines the luminal surface of vascular tube”
The ins and outs of the epithelial to mesenchymal transition in health and disease. (2011, background): “In agreement with this, tumor oxygenation restores endothelia and reduces tumor intravasation and metastasis (Mazzone et al. 2009).”
Direct Signaling Between Platelets and Cancer Cells Induces an Epithelial-Mesenchymal-Like Transition and Promotes Metastasis (2011, background): “This implies that cells that have intravasated without losing their epithelial properties either via leaky blood vessels (Carmeliet and Jain, 2000; Mazzone et al., 2009) or via collective invasion mechanisms (Friedl and Gilmour, 2009) could acquire a mesenchymal phenotype during their transit in…”
Hypoxia-induced angiogenesis: good and evil. (2011, background): “These changes in EC shape, not numbers, do not affect primary tumor growth but improve tumor perfusion and oxygenation.(161) Inhibition of PHD2 in ECs would provide a conceptually different strategy to blocking angiogenesis, whereby tumor vessel function is improved by streamlining the EC layer and ”
Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases (2011, background): “Moreover, metastasis was reduced and the efficacy of chemotherapies and immune therapies was improve”