Subject Review The Unfolded Protein Response: A Novel Component of the Hypoxic Stress Response in Tumors

Hypoxia is a physiologically important endoplasmic reticulum (ER) stress that is present in all solid tumors. Numerous clinical studies have shown that tumor hypoxia predicts for decreased local control, increased distant metastases, and decreased overall survival in a variety of human tumors. Hypoxia selects for tumors with an increased malignant phenotype and increases the metastatic potential of tumor cells. Tumor cells respond to hypoxia and ER stress through the activation of the unfolded protein response (UPR). The UPR is an adaptive response to increase cell survival during ER stress. XBP-1 is a critical transcriptional regulator of this process and is required for tumor growth. Pancreatic ER kinase (PKR-like ER kinase) regulates the translational branch of the UPR and is also important in the growth of tumors. Although the exact mechanism has yet to be elucidated, recent data suggest that the UPR affects tumor growth through protection from apoptosis and may influence angiogenic signaling pathways. Targeting various components of the UPR is a promising therapeutic strategy. Understanding the relationship between hypoxia, the UPR, and tumor growth is crucial to improving current cancer therapies. (Mol Cancer Res 2005;3(11):597–605