Metformin against Cancer Stem Cells through the Modulation of Energy Metabolism: Special Considerations on Ovarian Cancer

Figure 1

Mechanism of action of metformin in the concept of dynamic cancer stem cells in ovarian cancer. In contrast to the hierarchically organized cancer stem cell (CSC) model, the dynamic CSC model represents bidirectional interconversion between CSC and differentiated non-CSC states. The acquisition and maintenance of CSC characteristics are affected by microenvironmental cues, including inflammation, stromal cells and hypoxia, and therapeutics, such as chemotherapy. These factors eventually constitute the CSC niche (gray field). Hypoxia, which causes glycolysis, maintains and upregulates ovarian CSCs characteristics. Chemotherapy kills rapidly proliferating nontumorigenic cells, sparing chemoresistant CSCs. Chemotherapy also induces the acquisition of stem cell characteristics via epithelial-mesenchymal transition. Many studies using embryonal stem cells and induced pluripotent stem cells have demonstrated that glycolysis plays a fundamental role in inducing stemness. It is hypothesized that glycolysis may have a critical role in acquiring the CSC phenotype. It remains to be elucidated whether the metabotype is different between tumorigenic CSCs and rapidly proliferating nontumorigenic cells. Assumptive mechanisms of metformin’s synergic effect on chemotherapy and selective toxicity to CSCs are illustrated. Metabolic stress caused by metformin may inhibit the transition to the glycolytic phenotype, resulting in the prevention of the acquisition of stemness and dedifferentiation. Metformin may also target the inflammatory components present in the tumor microenvironment. Ovarian CSCs may lack the ability to cope with metabolic stress caused by metformin and glucose starvation.