The stressful conditions in the tumor microenvironment including low oxygen supply, nutrient deprivation and pH changes activate a range of cellular stress-response pathways. Tumor hypoxia is a common tumor microenvironmental factor that adversely influences tumor phenotype and treatment response. Cellular adaptation to hypoxia occurs through multiple mechanisms, including activation of the unfolded protein response (UPR). The UPR is an essential cellular process that regulates protein homeostasis, ensuring proper folding and function of proteins within the endoplasmic reticulum (ER). Disruptions in this response have been linked to the development and progression of human diseases, including cancer. The ER serves as a vital organelle involved in the synthesis, folding, and maturation of secretory and membrane proteins. Various cellular stressors, such as nutrient deprivation, hypoxia, and disturbances in calcium homeostasis, can lead to the accumulation of unfolded/misfolded proteins within the ER. In response to these conditions, cells activate the UPR to restore ER homeostasis and promote cell survival. The UPR is mediated by three major signaling pathways: IRE1, PERK and ATF6. These pathways coordinate adaptive cellular responses, by the upregulation of ER chaperones, attenuation of protein translation, and enhancement of protein degradation pathways.
Emerging evidence suggests that dysregulation of the UPR contributes to tumor initiation, progression, and therapeutic resistance in various types of human cancer. Aberrant activation or inhibition of specific UPR components can disrupt balance between cell survival and death, resulting in an environment conducive to tumor growth. Since UPR can trigger pro-survival and pro-apoptotic signals, it is important to understand how modulation of the UPR alters the equilibrium between these processes and contributes to tumorigenesis and therapy resistance. Studying the UPR and its implications in human cancer holds paramount importance for several reasons such as identification of therapeutic targets, prognostic and diagnostic biomarkers and unveiling underlying molecular mechanisms.
We welcome all types of submissions including:
- Original Research Articles (presenting new findings on the dysregulation of the UPR in specific cancer types, molecular mechanisms, and therapeutic potential;
- Review Articles (summarizing the current state of knowledge between the UPR and human cancer, recent advances, identifying knowledge gaps),
- Perspective Articles (offering expert insights and analysis on the future directions of research in understanding the UPR-cancer);
- Case Studies (presenting clinical cases analysis of the UPR pathway, diagnostic or prognostic information for cancer patients).
