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Review
. 2024 Apr 10:15:1375993.
doi: 10.3389/fphar.2024.1375993. eCollection 2024.

Metabolic vulnerability of cancer stem cells and their niche

Laura Marrone  1 , Simona Romano  1 , Chiara Malasomma  1 , Valeria Di Giacomo  1 , Andrea Cerullo  1 , Rosetta Abate  1 , Marialuisa Alessandra Vecchione  1 , Deborah Fratantonio  2 , Maria Fiammetta Romano  1
Affiliations
Review

Metabolic vulnerability of cancer stem cells and their niche

Laura Marrone et al. Front Pharmacol. .

Abstract

Cancer stem cells (CSC) are the leading cause of the failure of anti-tumor treatments. These aggressive cancer cells are preserved and sustained by adjacent cells forming a specialized microenvironment, termed niche, among which tumor-associated macrophages (TAMs) are critical players. The cycle of tricarboxylic acids, fatty acid oxidation path, and electron transport chain have been proven to play central roles in the development and maintenance of CSCs and TAMs. By improving their oxidative metabolism, cancer cells are able to extract more energy from nutrients, which allows them to survive in nutritionally defective environments. Because mitochondria are crucial bioenergetic hubs and sites of these metabolic pathways, major hopes are posed for drugs targeting mitochondria. A wide range of medications targeting mitochondria, electron transport chain complexes, or oxidative enzymes are currently investigated in phase 1 and phase 2 clinical trials against hard-to-treat tumors. This review article aims to highlight recent literature on the metabolic adaptations of CSCs and their supporting macrophages. A focus is provided on the resistance and dormancy behaviors that give CSCs a selection advantage and quiescence capacity in particularly hostile microenvironments and the role of TAMs in supporting these attitudes. The article also describes medicaments that have demonstrated a robust ability to disrupt core oxidative metabolism in preclinical cancer studies and are currently being tested in clinical trials.

Keywords: anti-mitochondrial drugs in clinical trials; cancer stem cells; oxidative metabolism; tumor associated macrophages; tumor dormancy.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
The prevalent metabolism adaptations in differentiated tumor cells compared to stem cell-like tumor cells support a metabolic symbiosis between the different cellular states. The illustration was started from scratch, created with BioRender.com original design.
FIGURE 2
FIGURE 2
Metabolic aspects of TAMs in tumor dormancy and reawakening. The illustration was started from scratch, created with BioRender.com original design.
FIGURE 3
FIGURE 3
Metabolic features of TAMs in CSC niche. The illustration was started from scratch, created with BioRender.com original design.
FIGURE 4
FIGURE 4
Mechanisms of the mitochondrial drugs used in clinical trials that have been shown to target CSCs in preclinical setting (https://www.clinicaltrials.gov). The illustration was started from scratch, created with BioRender.com original design.
See this image and copyright information in PMC

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