Title:Cell Metabolism Under Microenvironmental Low Oxygen Tension Levels in Stemness, Proliferation and Pluripotency
VOLUME: 15 ISSUE: 4
Author(s):M.P. De Miguel, Y. Alcaina, D. Sainz de la Maza and P. Lopez-Iglesias
Affiliation:Cell Engineering Laboratory, IdiPAZ, La Paz Hospital Research Institute, Paseo Castellana 261, Madrid 28046, Spain.
Keywords:Cancer, development, DNA repair, glycolisis, HIF, hypoxia, metabolism, reprogramming, ROS, stemness.
Abstract:Hypoxia is defined as a reduction in oxygen supply to a tissue below physiological
levels. However, physiological hypoxic conditions occur during early embryonic development;
and in adult organisms, many cells such as bone marrow stem cells are located within
hypoxic niches. Thus, certain processes take place in hypoxia, and recent studies highlight
the relevance of hypoxia in stem cell cancer physiology. Cellular response to hypoxia
depends on hypoxia-inducible factors (HIFs), which are stabilized under low oxygen
conditions. In a hypoxic context, various inducible HIF alpha subunits are able to form dimers
with constant beta subunits and bind the hypoxia response elements (HRE) in the genome,
acting as transcription factors, inducing a wide variety of gene expression. Typically, the HIF pathway has been
shown to enhance vascular endothelial growth factor (VEGF) expression, which would be responsible for
angiogenesis and, therefore, re-oxygenation of the hypoxic sites. Embryonic stem cells inhibit a severely
hypoxic environment, which dictates their glycolytic metabolism, whereas differentiated cells shift toward the
more efficient aerobic respiration for their metabolic demands. Accordingly, low oxygen tension levels have
been reported to enhance induced pluripotent stem cell (iPS) generation. HIFs have also been shown to
enhance pluripotency-related gene expression, including Oct4 (Octamer-binding transcription factor 4), Nanog
and Wnt. Therefore, cell metabolism might play a role in stemness maintenance, proliferation and cell
reprogramming. Moreover, in the hypoxic microenvironment of cancer cells, metabolism shifts from oxidative
phosphorylation to anaerobic glycolysis, a process known as the Warburg effect, which is involved in cancer
progression and malignancy.
