Oxygen-sensing in tumors

Tumor hypoxia induces cancer cell treatment resistance, angiogenesis, invasiveness, and overall poor clinical outcome. Cellular adaptations to hypoxia are largely driven by hypoxia-induced alterations in gene transcription, mRNA translation, and protein stability. This review will summarize recent advances in the understanding of mammalian oxygen-sensing mechanisms in normal and cancerous cells.

Specific molecular candidates have been identified that are involved in the primary sensing of hypoxia or its secondary consequences. Chief amongst these are the iron and 2-oxoglutarate-dependent dioxygenases that hydroxylate the alpha subunits of hypoxia-inducible transcription factors. This oxygen-dependent reaction, which prevents the transcription of many genes, is relieved under hypoxia. Evidence for the regulated expression and decay of the hypoxia-inducible transcription factor hydroxylating enzymes suggests that the sensitivity of transcriptional responses to hypoxia can be dynamically adjusted. Recent results also argue that these hydroxylating enzymes may be able to sense not only oxygen availability, but also the accumulation of bioenergetic intermediates and reactive oxygen species. In cancer cells, changes in these metabolites may accompany hypoxia or may occur independently. Several organellar compartments including plasma membrane, mitochondria and endoplasmic reticulum also appear to contribute to oxygen sensing through the generation of metabolites or through regulation of protein translation.

Oxygen-sensing mechanisms induce prominent clinically relevant changes in cancer cells and tumor biology through the control of gene expression. Significant overlap exists between oxygen-sensing mechanisms and other metabolic and cell stress sensing pathways, which allows nonhypoxic cell stresses to activate hypoxia-inducible responses.