Hypoxia signaling pathways in cancer metabolism: the importance of co-selecting interconnected physiological pathways

Both tumor hypoxia and dysregulated metabolism are classical features of cancer. Recent analyses have revealed complex interconnections between oncogenic activation, hypoxia signaling systems and metabolic pathways that are dysregulated in cancer. These studies have demonstrated that rather than responding simply to error signals arising from energy depletion or tumor hypoxia, metabolic and hypoxia signaling pathways are also directly connected to oncogenic signaling mechanisms at many points. This review will summarize current understanding of the role of hypoxia inducible factor (HIF) in these networks. It will also discuss the role of these interconnected pathways in generating the cancer phenotype; in particular, the implications of switching massive pathways that are physiologically 'hard-wired’ to oncogenic mechanisms driving cancer.