Hypoxia Signaling and the Metastatic Phenotype
H. Mujcic, R.P. Hill, M. Koritzinsky and B.G. Wouters
Pages 565-579 (15)
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.
Cancer, HIF, hypoxia, LAMP3, metastasis, UPR.
Princess Margaret Cancer Centre and Campbell Family Institute for Cancer Research, University Health Network, 610 University Ave, Toronto, ON M5G 2M9, Canada.