[Metastasis and hypoxia-inducible factor]

Cancer cells undergo distinct responses including anaerobic metabolism and angiogenesis, to cope with their hypoxic environment. These responses are achieved at least partly by the action of transcriptional factors, which are called hypoxiainducible factors (HIFs). HIFs consist of a constitutively expressed subunit of HIF-1beta and an oxygen-regulated subunit of HIF-1alpha (or HIF-2alpha and HIF-3alpha). In hypoxia, an HIF-1alpha subunit becomes stable and regulates the expression of target genes. Clinical and experimental evidence suggest that altered gene expression induced by HIFs in response to the hypoxic microenvironment is a contributing factor to increasing metastatic efficiency. Diffusion-limited hypoxia, a consequence of tumor cells that are distant from the vascular supply, was the original concept behind hypoxia in tumors, and it was suggested that perfusion-limited hypoxia(acute or fluctuating hypoxia), due to fluctuations in blood flow, might play an important role in tumors. However, the effects of fluctuating hypoxia on gene expression induced by HIFs have yet to be addressed. In the present review, we focus on a number of genes that have been implicated in the metastatic process, and have been found to be hypoxia-responsive.