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

Mazzone et al.  Cell 136, 1–13, 2009

Speaker: Shuo-Fu Lin (林碩甫)                                            Time: 15:00~16:00, May 20, 2009

Commentator: Prof. Cheng-Chan Lu (呂政展 教授)           Place: Room 601

Abstract:

       Over the limits of diffusion, tumor maintenance depends on a sufficient supply of oxygen and on removal of metabolic waste by the blood. When blood vessels cannot supply enough oxygen, tumor cells invade the surrounding normal tissue to look for oxygen and might even metastasize to other tissues. Endothelial cells arrange blood vessels and thus are the door to tissue oxygenation. This study focuses on an element of cellular oxygen sensing called prolyl hydroxylase domain protein 2 (PHD2). PHD2 targets the hypoxia-inducible factors (HIFs) for degradation¹. During hypoxia, PHD proteins are less active, so that HIFs can be stabilized, resulting in triggering the expression of vascular endothelial growth factor (VEGF)², a major angiogenic stimulus that is used by tumors and normal tissues. In this study, the authors identified the PHD2 protein as a key regulator of oxygen supply to tumors and suggested that it may be involved in the shaping of blood-vessel networks. The authors generated mice lacking one of the two copies of the PHD2 gene. They found that tumors grown either in normal mice or in PHD2+/- mice exhibit similar growth rates. However, the vascular morphology of tumors was strikingly different. In normal mice, tumors had disordered, poorly perfused blood vessels, which resulted in a low-oxygen environment and high VEGF production. By contrast, tumor vessels in PHD2+/- mice resembled normal blood vessels, resulting inimproved tumor perfusion and oxygenation, as well as inhibited tumor cell invasion, intravasation, and metastasis. Moreover, these normalized vessels contributed to better oxygenation of the tumor, which in turn led to less VEGF production and reduced response of these cells to VEGF by increasing the expression of soluble VEGF receptor-1 (sVEGFR-1) and VE-cadherin. These factors, which are regulated by PHD2, can normalize endothelial function. In conclusion, blood vessel normalization  affects tumor invasion and metastasis, suggesting that endothelial oxygen sensing may represent a new target of cancer therapy.

References:

1.      Semenza GL et al. 2003. Targeting HIF-1 for cancer therapy. Nat. Rev. Cancer 3: 721–732.

2.      Qing G & Simon MC. 2009. Hypoxia inducible factor-2α: a critical mediator of aggressive tumor phenotypes. Curr. Opin. Genet. Dev. 19: 1–7.