Hypoxia Signaling and the Metastatic Phenotype

Conditions of poor oxygenation (hypoxia) are present in the majority of solid human tumors and are associated with poor patient prognosis due to both hypoxia-mediated resistance to treatment, and to hypoxiainduced biological changes that promote increased malignancy, including metastasis. Tumor cells respond to hypoxia by activating several oxygen-sensitive signaling pathways that include the hypoxia inducible factor 1/2 (HIF1/2) signalling pathways and the unfolded protein response (UPR), which alter gene expression to promote adaptation and survival during hypoxic conditions. Furthermore, these hypoxia responsive pathways can lead to changes in gene expression and cellular phenotype that influence the potential of cancer cells to metastasize. However, the hypoxia-induced signaling events that promote tumor metastasis are still relatively poorly understood. Previous studies have largely focused on the contribution of the HIF signaling pathway to hypoxia-mediated metastasis. However, recent evidence demonstrates that hypoxic activation of the UPR is also an important mediator of metastasis.