The potential role of HIF on tumour progression and dissemination.

Cancer is the second cause of mortality worldwide, primarily owing to failure to cure metastatic disease. The need to target the metastatic process to reduce mortality is clear and research over the past decade has shown hypoxia-inducible factor-1 (HIF-1) to be one of the promising targets. In order for metastatic disease to be established, multiple steps need to be taken whereby the tumour cells escape into the bloodstream and survive, disseminate and then establish at a premetastatic niche. HIF-1 mediates hypoxia-induced proangiogenic factors such as vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF), which promote extravasation and chemotaxis. The migration of tumour cells is mediated by loss of E-cadherin, which results in a more invasive phenotype; dissemination of the tumour cells by increased vascular permeability and survival in the bloodstream through resistance to apoptosis as well as adhesion at the premetastatic niche are all controlled by factors under the influence of HIF-1. The overexpression of HIF in many aggressive cancer types as well as its role in the establishment of metastatic disease and treatment resistance demonstrate its potential target in therapeutics. Taken together, the role of HIF-1 in cancer and metastatic disease is clear and the need for better treatment targeting metastases is paramount; more aggressive phenotypes with less response to treatment are associated with HIF-1 expression. Our research has shown promise but many questions still remain to be answered.