title: Endothelial oxygen sensors regulate tumor vessel abnormalization by instructing phalanx endothelial cells.
abstract: An ancestral function of vessels is to conduct blood flow and supply oxygen (O(2)). In hypoxia, cells secrete angiogenic factors to initiate vessel sprouting. Angiogenic factors are balanced off by inhibitors, ensuring that vessels form optimally and supply sufficient oxygen (O(2)). By contrast, in tumors, excessive production of angiogenic factors induces vessels and their endothelial cell (EC) layer to become highly abnormal, thereby impairing tumor perfusion and oxygenation. In such pathological conditions, angiogenic factors act as "abnormalization factors" and promote the vessel "abnormalization switch." Recent genetic data indicate that ECs sense an imbalance in oxygen levels, by using the oxygen-sensing prolyl hydroxylase PHD2. In conditions of O(2) shortage, a decrease in PHD2 activity in ECs initiates a feedback that restores their shape, not their numbers. This induces ECs to align in a streamlined "phalanx" of tightly apposed, regularly ordered cobblestone ECs, which improves perfusion and oxygenation. As a result, EC normalization in PHD2 haplodeficient tumor vessels improves oxygenation and renders tumor cells less invasive and metastatic. This review discusses the role of PHD2 in the regulation of vessel (ab)normalization and the therapeutic potential of PHD2 inhibition for tumor invasiveness and metastasis.
authors.affiliation: Vesalius Research Center, K.U. Leuven, Belgium.
authors.forename: Katrien
authors.initials: K
authors.lastname: De Bock
authors.forename: Frederik
authors.initials: F
authors.lastname: De Smet
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Leite De Oliveira
authors.forename: Kristof
authors.initials: K
authors.lastname: Anthonis
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D004730:Endothelium, Vascular / Q000166:cytology / Q000473:pathology* / Q000648:ultrastructure; D006801:Humans; D008954:Models, Biological; D009369:Neoplasms / Q000098:blood supply* / Q000473:pathology* / Q000648:ultrastructure; D010100:Oxygen / Q000378:metabolism*; D011393:Procollagen-Proline Dioxygenase / Q000378:metabolism
chemical_list: D011393:Procollagen-Proline Dioxygenase; D010100:Oxygen