Endoplasmic Reticulum Stress and the Hallmarks of Cancer

Highly proliferative tumors are exposed to several intrinsic and extrinsic factors that induce adaptation to stress conditions. ER stress is a common feature of different types of blood and solid cancers. Adaptation to ER stress is achieved by the activation of the UPR. The UPR is involved in the acquisition of several malignant characteristics that allow tumor growth. ER stress signaling also occurs in stromal cells such as endothelial, macrophage, and dendritic cells, suggesting a novel concept of ‘transmissible ER stress’. Although the acquisition of tumor characteristics is driven by UPR signaling events, some of these features are independent of ER stress, as observed in angiogenesis and tumor-promoting inflammation. Several specific small molecules that inhibit UPR stress sensors (IRE1α and PERK) have beneficial effects in multiple myeloma and pancreatic cancer. Tumor cells are often exposed to intrinsic and external factors that alter protein homeostasis, thus producing endoplasmic reticulum (ER) stress. To cope with this, cells evoke an adaptive mechanism to restore ER proteostasis known as the unfolded protein response (UPR). The three main UPR signaling branches initiated by IRE1α, PERK, and ATF6 are crucial for tumor growth and aggressiveness as well as for microenvironment remodeling or resistance to treatment. We provide a comprehensive overview of the contribution of the UPR to cancer biology and the acquisition of malignant characteristics, thus highlighting novel aspects including inflammation, invasion and metastasis, genome instability, resistance to chemo/radiotherapy, and angiogenesis. The therapeutic potential of targeting ER stress signaling in cancer is also discussed. Tumor cells are often exposed to intrinsic and external factors that alter protein homeostasis, thus producing endoplasmic reticulum (ER) stress. To cope with this, cells evoke an adaptive mechanism to restore ER proteostasis known as the unfolded protein response (UPR). The three main UPR signaling branches initiated by IRE1α, PERK, and ATF6 are crucial for tumor growth and aggressiveness as well as for microenvironment remodeling or resistance to treatment. We provide a comprehensive overview of the contribution of the UPR to cancer biology and the acquisition of malignant characteristics, thus highlighting novel aspects including inflammation, invasion and metastasis, genome instability, resistance to chemo/radiotherapy, and angiogenesis. The therapeutic potential of targeting ER stress signaling in cancer is also discussed. a dynamic tubular network involved in metabolic processes including gluconeogenesis, lipid synthesis, and the biogenesis of autophagosomes and peroxisomes. It is also the major intracellular calcium reservoir. a cellular condition generated when misfolded proteins accumulate inside the ER. a pathway to eliminate misfolded proteins along which proteins are transported from the ER to the cytosol for further degradation by the proteasome. a portmanteau of the words protein and homeostasis. Refers to the concept of integrated biological pathways within cells that control the biogenesis, folding, trafficking, and degradation of intracellular and extracellular proteins. pernicious condition generated by an exacerbated increase of proteins or the presence of misfolded proteins. the degradation of a subset of mRNAs encoding proteins located in the ER and microRNAs through the activation of the endoRNase domain of IRE1. a series of adaptive mechanisms triggered by ER stress to cope with protein-folding alterations through the transcriptional regulation of proteins involved in folding and clearance to restore ER proteostasis.