The impact of O2 availability on human cancer

Abstract

During the past century it has been established that regions within solid tumours experience mild to severe O(2) deprivation owing to aberrant vascular function. These hypoxic regions are associated with altered cellular metabolism, as well as increased resistance to radiation and chemotherapy. As discussed in this Timeline, over the past decade work from many laboratories has elucidated the mechanisms by which hypoxia-inducible factors (HIFs) modulate tumour cell metabolism, angiogenesis, growth and metastasis. The central role played by intra-tumoural hypoxia and HIF in these processes has made them attractive therapeutic targets in the treatment of multiple human malignancies.

Figure 1

Genes activated by hypoxia-inducible factors (HIFs) involved in tumor progression. Genes encoding proteins involved in numerous aspects of tumor initiation, growth, and metastasis are transcriptionally activated by either encoding HIF-1α or HIF-2α. Examples include: inflammatory cell recruitment (SDF-1α, CXCR4), proliferation (cyclin-D2, IGF-2), survival (VEGF, erythropoietin), metabolism/mitochondrial function (glycolytic enzymes, PDK-1), extracellular matrix function (fibronectin-1, collagen type-5), motility (c-MET, SPF-1α), angiogenesis (VEGF, PDGF), and pH regulation (carbonic anhydrase-9).

Figure 2

Regulation of HIF-α subunits by O₂ availability and other intracellular metabolites. In oxygen replete cells, the HIF-prolyl hydroxylases (PHDs) are active, resulting in the hydroxylation of proline residues in HIF-α and their targeted degradation via the pVHL-proteosome pathway. “Factor-inhibiting HIF” (FIH) hydroxylation of an asparagine residue in the C-terminus of the HIF-α subunit, blocks p300 co-factor recruitment. This results in the inactivation of HIF-α subunit transcriptional activity. All of these processes are inhibited when O₂ levels decrease or cells exhibit increased levels of reactive oxygen species (ROS) and other metabolites such as fumerate, succinate, and nitric oxide (NO). Here, the HIF-α subunits are stabilized, they recruit co-activators such as p300, and activate HIF target genes, as described in Figure 1.

Figure 3

Hypoxia regulates other critical pathways that impact tumor progression in a HIF-independent fashion. A schematic diagram of signaling pathways which regulate mRNA translation is shown. These include the mTOR pathway and the integrated stress response. Hypoxia influences AMPK and REDD1 activity, which act upstream to inhibit mTOR kinase activity, resulting in a decrease in cap-dependent translation. Hypoxia also inhibits the ER resident kinase PERK, which phosphorylates eIF2α, resulting in global protein synthesis inhibition. While HIFs contribute to mTOR regulation via the induction of REDD1 during chronic hypoxia, all of these pathways can be regulated by O₂ deprivation in a HIF-independent manner. Although the mechanisms for mTOR and PERK regulation by changes in O₂ remain unclear, they represent important additional therapeutic targets.