Abstract
Cancer stem cells (CSCs) are a distinct subpopulation of tumor cells with stem cell-like features. Able to initiate and sustain tumor growth and mostly resistant to anti-cancer therapies, they are thought responsible for tumor recurrence and metastasis. Recent accumulated evidence supports that iron metabolism with the recent discovery of ferroptosis constitutes a promising new lead in the field of anti-CSC therapeutic strategies. Indeed, iron uptake, efflux, storage and regulation pathways are all over-engaged in the tumor microenvironment suggesting that the reprogramming of iron metabolism is a crucial occurrence in tumor cell survival. In particular, recent studies have highlighted the importance of iron metabolism in the maintenance of CSCs. Furthermore, the high concentration of iron found in CSCs, as compared to non-CSCs, underlines their iron addiction. In line with this, if iron is an essential macronutrient that is nevertheless highly reactive, it represents their Achilles’ heel by inducing ferroptosis cell death and therefore providing opportunities to target CSCs. In this review, we first summarize our current understanding of iron metabolism and its regulation in CSCs. Then, we provide an overview of the current knowledge of ferroptosis and discuss the role of autophagy in the (regulation of) ferroptotic pathways. Finally, we discuss the potential therapeutic strategies that could be used for inducing ferroptosis in CSCs to treat cancer.
Highlights
The pathways of iron uptake, storage, mobilization, trafficking, and regulation are all perturbed in cancer, suggesting that the reprogramming of iron metabolism is a central aspect of tumor cell survival
Characterized by several markers (CD44, CD24, ALDH1, and CD133 which are summarized in Table 1; for a review, please see [8]), cancer stem cells (CSCs) are subpopulations of cancer cells within liquid and solid tumors that share similar features to those of normal progenitor/stem cells, such as self-renewal and multi-lineage differentiation abilities, which drive the tumor growth and heterogeneity
Iron exportation is regulated at the systemic level by hepcidin by binding FPN
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Recent studies have shed light on the role of iron metabolism in cancer stem cells (CSCs) and suggested that the specific targeting of iron metabolism in CSCs may improve the efficacy of cancer therapy. This iron dependency can make CSC and non-CSC cells more vulnerable to a newly identified form of programmed cell death, referred to as ferroptosis. Metabolic reprogramming has been linked to an acquired sensitivity to ferroptosis, opening new opportunities to treat tumors that are unresponsive to other conventional therapies
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