Redox regulation of cancer stem cells: Biology and therapeutic implications

Cancer stem cells (CSCs) are a small group of tumor cells with the capacity to undergo self-renewal and differentiation. These cells not only initiate and maintain tumor growth, but also confer resistance to current cancer therapies. CSCs display a high degree of plasticity and can be generated under therapeutic stress via dedifferentiation from non-stem-like tumor cells, suggesting the necessity simultaneously targeting CSCs and bulk tumor cells to achieve the best therapeutic effect. Despite the findings that therapeutic stress induces CSC plasticity, the mechanisms underpinning CSC formation and therapeutic resistance are not fully defined. Tumor cells display elevated levels of reactive oxygen species (ROS), contributed by rapid proliferation, enhanced metabolic demands and oncogenic signaling. CSCs achieve redox homeostasis partly by regulating redox-sensitive transcription factors (TFs), including NRF2, HIF-1 alpha, BACH1, NF-kB, FOXOs, AP-1, and others. This review aims to summarize the roles and underlying mechanisms of these TFs in regulation of CSCs and tumor progression from the perspectives of stem cell maintenance, metabolic reprogramming, epithelial-mesenchymal transition (EMT) and angiogenesis. We also discuss the potentials of utilizing specific inhibitors for these TFs in suppressing drug resistance and metastasis by repressing CSC activity, an approach that may provide new targeted therapies for advanced cancer and improve patient outcome.