Assessment of tumour hypoxia for prediction of response to therapy and cancer prognosis

• Introduction • Pathological markers of hypoxia - Necrosis - Hypoxia inducible factor (HIF) targets - HIF-1 versus HIF-2 - Early versus late stage cancer - Intratumour heterogeneity - Quality of reports and heterogeneity • Molecular signatures of hypoxia - Comparison of tumour with in vitro hypoxic response profiles - In vivo clustering with seed genes - MicroRNAs • Markers of hypoxia and response to treatment • Concluding remarks Tumour cells exploit both genetic and adaptive means to survive and proliferate in hypoxic microenvironments, resulting in the outgrowth of more aggressive tumour cell clones. Direct measurements of tumour oxygenation, and surrogate markers of the hypoxic response in tumours (for instance, hypoxia inducible factor-1α, carbonic anhydrase 9 and glucose transporter-1) are well-established prognostic markers in solid cancers. However, individual markers do not fully capture the complex, dynamic and heterogeneous hypoxic response in cancer. To overcome this, expression profiling has been employed to identify hypoxia signatures in cohorts or models of human cancer. Several of these hypoxia signatures have demonstrated prognostic significance in independent cancer datasets. Nevertheless, individual hypoxia markers have been shown to predict the benefit from hypoxia-modifying or anti-angiogenic therapies. This review aims to discuss the clinical impact of translational work on hypoxia markers and to explore future directions for research in this area.