Hypoxia, DNA repair and genetic instability

The presence of intratumoural hypoxia is a negative prognostic indicator for many patients as it has been associated with increased local failure following radiotherapy and increased distant metastatic spread.Hypoxia can drive the metastatic phenotype secondary to genetic instability, increased angiogenesis, decreased apoptosis and upregulation of a number of genes involved in the metastatic cascade (such as osteopontin, lysyl oxidase and vascular endothelial growth factor).Both acute and chronic hypoxia exist in human tumours and these may have different biological consequences as a function of changes in hypoxia-inducible factor 1α-mediated transcription, altered protein translation and differential activation of hypoxia-associated cell cycle checkpoints.Hypoxic cells can acquire a mutator phenotype that consists of decreased DNA repair, an increased mutation rate and increased chromosomal instability.Defects in homologous recombination and mismatch repair have been documented in tumour cells that are exposed to chronic hypoxia.Defective DNA repair in hypoxic cells could alter the sensitivity to radiotherapy and chemotherapy and render cells susceptible to molecular-targeted agents that are selectively toxic to checkpoint-deficient or repair-deficient tumour cells.