Targeting Cancer Stem Cell Redox Metabolism to Enhance Therapy Responses

Cancer has long been viewed as a disease of altered metabolism. Although it has long been recognized that the majority of cancer cells display increased dependence on glycolysis, the metabolism of "cancer stem-like cells" (CSCs) that drive tumor growth and metastasis is less well characterized. In this chapter, we review the current state of knowledge of CSC metabolism with an emphasis on the development of therapeutic strategies to exploit the metabolic vulnerabilities of these cells. We outline emerging evidence indicating distinct metabolic pathways active in the proliferative, epithelial- (E) and quiescent, mesenchymal-like (M) CSC states in triple negative breast cancer. These CSC states are characterized by their different redox potentials and divergent sensitivities to inhibitors of glycolysis and redox metabolism. We highlight the roles of two redox-regulated signaling pathways, hypoxia-inducible factor 1α and nuclear factor erythroid 2-related factor 2, in regulating CSC epithelial-mesenchymal plasticity during metabolic and/or oxidative stress, and discuss clinical strategies using combinations of pro-oxidant-based therapeutics simultaneously targeting E- and M-like CSCs. By specifically targeting CSCs of both states, these strategies have the potential to increase the therapeutic efficacy of traditional chemotherapy and radiation therapy.