PHD2 in tumour angiogenesis

Abstract

Originally identified as the enzymes responsible for catalysing the oxidation of specific, conserved proline residues within hypoxia-inducible factor-1alpha (HIF-1alpha), the additional roles for the prolyl hydroxylase domain (PHD) proteins have remained elusive. Of the four identified PHD enzymes, PHD2 is considered to be the key oxygen sensor, as knockdown of PHD2 results in elevated HIF protein. Several recent studies have highlighted the importance of PHD2 in tumourigenesis. However, there is conflicting evidence as to the exact role of PHD2 in tumour angiogenesis. The divergence seems to be because of the contribution of stromal-derived PHD2, and in particular the involvement of endothelial cells, vs tumour-derived PHD2. This review summarises our current understanding of PHD2 and tumour angiogenesis, focusing on the influences of PHD2 on vascular normalisation and neovascularisation.

Figure 1

In the presence of oxygen, a family of prolyl hydroxylases oxidises HIF-1α, leading to interaction with VHL and subsequent degradation. Conversely, when the prolyl hydroxylases are not active, HIF-1α is stabilised, interacts with HIF-1β, and is transcriptionally active.

Figure 2

(A) Loss of PHD2 in a tumour results in activation of NF-κB. In turn, NF-κB upregulates ANG and IL-8 that promote both angiogenesis and bone marrow-derived cell recruitment. These two complementary pathways drive tumour growth. (B) Tumours implanted into Phd2^+/+ mice have irregular and leaky vessels, whereas those implanted into Phd2^+/− mice have ‘normalised’ vessels.