The hypoxic microenvironment of tumours, acting via hypoxia inducible factor 1α (HIF-1α), might promote the angiogenic stimulation required for cancer development, with a resultant aggressive cell phenotype and rapid malignant progression. 1 In their recent article, Marignol et al. 2 described the importance of notch signalling pathways in differentiation, proliferation, angiogenesis, vascular remodelling and apoptosis in prostate cancer (Marignol, L., Rivera-Figueroa, K., Lynch, T. & Hollywood, D. Hypoxia, notch signalling, and prostate cancer. Nat. Rev. Urol. 10, 405–413; 2013). The Review highlighted similarities between notch-activated and hypoxic prostate cancer cells. We believe that normoxic HIF-1α expression in prostate cancer, is equally important to—if not more important than—hypoxia mediated by HIF-1α. Indeed, a better understanding of the former would lead to improved prognostication and, potentially, reduced treatment resistance in men with this disease.

Although HIF-1α has a key role in the physiological response to hypoxia, its importance in cancers is less clear. High expression of HIF-1α in some cancer cell lines (for example, renal and breast cancers) has been shown to increase angiogenesis and cancer cell survival, whereas in other cancers (such as ovarian carcinoma), high HIF-1α concentrations contribute to increased apoptosis. 3 In prostate cancer, HIF-1α overexpression has been linked with shorter time to biochemical recurrence in patients receiving radiotherapy or surgery, castration resistance, chemoresistance and metastasis. 4, 5, 6 Although hypoxia is a strong driver of HIF-1α expression, and the presence of hypoxic regions has been shown in many human tumours, the localized expression of HIF-1α and its downstream targets only in the hypoxic areas of tumours has been difficult to demonstrate. 7 Furthermore, it has been consistently difficult to demonstrate localized hypoxia, particularly in high-grade prostate cancer; consequently, HIF-1α expression is thought to be independent of hypoxia. 8