Hypoxia mediated signaling pathways

Hypoxia mediated signaling pathways play important roles in the development of cancer and the response of tumors to conventional therapies. These pathways, including the HIF signaling cascade and the unfolded protein response, represent potential new avenues for targeted treatments. Hypoxia, or low oxygen conditions, exists in virtually all solid tumors. Chemotherapeutic agents are less active on hypoxic cells since hypoxic cells proliferate slower than well-perfused tissues. Similarly, the efficacy of radiation treatment is directly correlated with oxygenation status of a tumor. At both the molecular and cellular levels, in physiological and pathological settings, oxygen homeostasis is controlled primarily through the function of a heterodimeric transcription factor, the hypoxia inducible factor-1 (HIF-1). HIF signaling occurs at different stages of metastasis to promote the dissemination of primary tumor cells to distant sites. The key step in the development of metastasis is the epithelial-mesenchymal transition (EMT), whereby epithelial cells lose cell contacts and polarity and phenotypically become more like undifferentiated connective tissue. Prolonged periods of hypoxia can activate additional non-HIF signaling pathways, including the unfolded protein response (UPR). The UPR is a cellular stress response that is induced by the accumulation of unfolded proteins in the endoplasmic reticulum (ER) in order to process misfolded proteins. This is achieved twofold: by stopping protein translation to prevent further bottlenecks and through the induction of chaperone proteins that function in the ER to assist in folding, trafficking, and secretion of proteins. © 2010 Elsevier Inc. All rights reserved.