Regulation of Metabolic Plasticity in Cancer Stem Cells and Implications in Cancer Therapy

Simple Summary Glucose is the main fuel cell used for energy production via a series of enzymatic reactions in the presence of oxygen in a process known as aerobic respiration. The main steps in this process are glycolysis, the tricarboxylic acid cycle, and oxidative phosphorylation (OXPHOS). Cancer cells rely mostly on glycolysis and less on OXPHOS for rapid production of energy and intermediate macromolecules that are required to sustain their increased proliferation rate. This metabolic reprogramming is considered one of the hallmarks of cancer and has been linked to tumor growth and progression, as well as to the development of therapy resistance. Cancer stem cells (CSCs) are a subset of tumor cells with self-renewal and differentiation capacities and have gained much attention due to their involvement in cancer initiation and resistance to conventional therapies. In contrast to the bulk of tumor cells, CSCs can switch between glycolysis and OXPHOS depending on stimuli from their microenvironment. This metabolic plasticity allows them to adapt and survive under various stressful conditions, maintaining, at the same time, their stemness properties, and, thus, contributing to the development of therapy resistance and tumor recurrence. Consequently, understanding the specific features of CSC metabolism is crucial for the successful elimination of these cells. In this review, we provide a concise description of the metabolic signatures of CSCs, emphasizing their metabolic plasticity and its involvement in drug resistance; we also draw attention to the potential of targeting CSC metabolism as a complementary therapeutic approach in cancer. Cancer stem cells (CSCs), a subpopulation of tumor cells with self-renewal capacity, have been associated with tumor initiation, progression, and therapy resistance. While the bulk of tumor cells mainly use glycolysis for energy production, CSCs have gained attention for their ability to switch between glycolysis and oxidative phosphorylation, depending on their energy needs and stimuli from their microenvironment. This metabolic plasticity is mediated by signaling pathways that are also implicated in the regulation of CSC properties, such as the Wnt/beta-catenin, Notch, and Hippo networks. Two other stemness-associated processes, autophagy and hypoxia, seem to play a role in the metabolic switching of CSCs as well. Importantly, accumulating evidence has linked the metabolic plasticity of CSCs to their increased resistance to treatment. In this review, we summarize the metabolic signatures of CSCs and the pathways that regulate them; we especially highlight research data that demonstrate the metabolic adaptability of these cells and their role in stemness and therapy resistance. As the development of drug resistance is a major challenge for successful cancer treatment, the potential of specific elimination of CSCs through targeting their metabolism is of great interest and it is particularly examined.