Abstract
While oxygen is critical to the continued existence of complex organisms, extreme levels of oxygen within a system, known as hypoxia (low levels of oxygen) and hyperoxia (excessive levels of oxygen), potentially promote stress within a defined biological environment. The consequences of tissue hypoxia, a result of a defective oxygen supply, vary in response to the gravity, extent and environment of the malfunction. Persistent pathological hypoxia is incompatible with normal biological functions, and as a result, multicellular organisms have been compelled to develop both organism-wide and cellular-level hypoxia solutions. Both direct, including oxidative phosphorylation down-regulation and inhibition of fatty-acid desaturation, and indirect processes, including altered hypoxia-sensitive transcription factor expression, facilitate the metabolic modifications that occur in response to hypoxia. Due to the dysfunctional vasculature associated with large areas of some cancers, sections of these tumors continue to develop in hypoxic environments. Crucial to drug development, a robust understanding of the significance of these metabolism changes will facilitate our understanding of cancer cell survival. This review defines our current knowledge base of several of the hypoxia-instigated modifications in cancer cell metabolism and exemplifies the correlation between metabolic change and its support of the hypoxic-adapted malignancy.
Highlights
Hypoxic regions, areas of reduced tissue oxygen levels, are found in many solid tumors occurring as a consequence of the disordered vasculature developed to supply oxygen to the rapidly growing tumor
Tumor cells are exposed to a continuum of oxygen concentrations and solid tumors are comprised of three tissue regions: the normoxic, hypoxic and necrotic (Figure 1)
There are four different views on the relationship between epigenetics and hypoxia: (1) hypoxia-inducible factor (HIF) stabilization is affected by the epigenetic control of von Hippel-Lindau (VHL) and PHD3 expression; (2) epigenetic pathways control HIF binding by ensuring a transcriptionally active chromatin configuration in and in the vicinity of HIF binding sites; (3) a major proportion of histone demethylase enzymes are direct HIF-1 target genes which play a major part in the control of transcription during responses to hypoxia; (4) major wide-reaching changes in histone alterations and DNA methylation take place following exposure to hypoxia (Watson et al, 2010; Wong et al, 2017)
Summary
Areas of reduced tissue oxygen levels, are found in many solid tumors occurring as a consequence of the disordered vasculature developed to supply oxygen to the rapidly growing tumor. As noted by Vaupel et al (2001) and Vaupel and Harrison (2004), the structural and functional abnormalities arising from the chaotic vasculature and structure of a tumor, including dilated, elongated and twisted blood vessels, poor endothelium, reduced functional cell receptors, no regulation of blood flow, which results in spontaneous stasis, result in poor oxygen delivery as a consequence of inadequate blood flow. This form of hypoxia is termed ischemic hypoxia and is generally transient (Vaupel et al, 2001; Vaupel and Harrison, 2004). Both acute and chronic hypoxia are correlated with poor patient outcome and an aggressive tumor phenotype (Williams et al, 2001; Vaupel and Harrison, 2004)
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