A normoxic mode of HIF-1α accumulation and angiogenesis via Pfn-1 phosphorylation in GBM

摘要

The tumor microenvironment orchestrates tumor progression in a complex fashion by secretion of factors that not only promote cancer cell growth but also proliferation of endothelial cells (ECs). Aberrant vascutarization is a hallmark of glioblastoma (GBM) and therapies directed at normalization of the vas-culature are currently being evaluated as an anti-cancer strategy. Hypoxic tumor microenvironments mediate stabilization of hypoxia-inducible factor-1 alpha (HIF-1α), which in turn promotes EC proliferation primarily due to the induction of angiogenic growth factors. Conversely, in the presence of oxygen, prolyl hydroxylation of HIF-1α by PHD dioxygenases creates a recognition signal for binding of the Von Hippel-Linadu (VHL) tumor supressor to HIF-1α and its subsequent ubiquitina-tion and degradation. Other studies, however, have shown stabilization of HIF-1α under normoxic conditions in a manner independent of VHL, although the exact mechanisms remain unclear.