Hypoxia‐inducible Factors in Stem Cells and Cancer

• Introduction • From metabolic adaptation to stem cell signalling • HIF-1α regulates Notch effects on cellular differentiation • Stem cell pluripotency requires HIF target gene function • O2 regulation of Wnt signalling is differentiation-stage specific • HIFs, stem cell pathways and disease • HIF and cMyc • HIF and p53 Cellular properties are influenced by complex factors inherent to their microenvironments. While oxygen deprivation (hypoxia) occurs in tumours because of rapid cell proliferation and aberrant blood vessel formation, embryonic cells develop in a naturally occurring hypoxic environment. Cells respond to hypoxia by stabilizing hypoxia-inducible factors (HIFs), which are traditionally viewed to function by altering cellular metabolism and blood vessel architecture. Recently, HIFs have been shown to modulate specific stem cell effectors, such as Notch, Wnt and Oct4 that control stem cell proliferation, differentiation and pluripotency. Direct molecular links have also been established between HIFs and critical cell signalling pathways such as cMyc and p53. These novel links suggest a new role for HIFs in stem cell and tumour regulation.