Metabolic Escape Routes of Cancer Stem Cells and Therapeutic Opportunities

Abstract

Although improvement in early diagnosis and treatment ameliorated life expectancy of cancer patients, metastatic disease still lacks effective therapeutic approaches. Resistance to anticancer therapies stems from the refractoriness of a subpopulation of cancer cells—termed cancer stem cells (CSCs)—which is endowed with tumor initiation and metastasis formation potential. CSCs are heterogeneous and diverge by phenotypic, functional and metabolic perspectives. Intrinsic as well as extrinsic stimuli dictated by the tumor microenvironment (TME)have critical roles in determining cell metabolic reprogramming from glycolytic toward an oxidative phenotype and vice versa, allowing cancer cells to thrive in adverse milieus. Crosstalk between cancer cells and the surrounding microenvironment occurs through the interchange of metabolites, miRNAs and exosomes that drive cancer cells metabolic adaptation. Herein, we identify the metabolic nodes of CSCs and discuss the latest advances in targeting metabolic demands of both CSCs and stromal cells with the scope of improving current therapies and preventing cancer progression.

Exosomes and Cancer Stem Cells in Cancer Immunity: Current Reports and Future Directions

“…EVs released from CSCs play multiple roles, not only by the surface expression of various markers but also by delivering cargo to the receiving cells in the tumor microenvironment (Figure 1) [52]. Exosomes released from CSCs deliver cargo that is thought to be responsible for establishing the pre-metastatic niche, thus contributing to increasing the metastatic potential of CSCs and other associated cells [53,54]. The content unique to tumor-derived exosomes [55].…”

“…Another example of prostate CDEXs with the surface expression of caveolin-1 was observed to transform CSCs into a metastatic phenotype via NF-κB signaling [ 105 ]. Furthermore, the interactions of CSCs with CAFs have been observed by using CAF-derived exosomes and their miRNA content, such as miR-21, miR-378e, and miR-143 [ 53 ]. These were also observed to promote tumor progression, except for miR-320, which antagonized the premetastatic niche formation [ 53 ].…”

“…Furthermore, the interactions of CSCs with CAFs have been observed by using CAF-derived exosomes and their miRNA content, such as miR-21, miR-378e, and miR-143 [ 53 ]. These were also observed to promote tumor progression, except for miR-320, which antagonized the premetastatic niche formation [ 53 ].…”

Targeting the Mitochondrial Metabolic Network: A Promising Strategy in Cancer Treatment

“…Strict reliance on OXPHOS represents a metabolic vulnerability of such cancer cells. In this regard, they can be treated with OXPHOS inhibitors, which in turn can resensitize cancer cells with acquired resistance to the respective targeted therapy [ 68 , 69 ].…”

Tumor Metabolome: Therapeutic Opportunities Targeting Cancer Metabolic Reprogramming

“…Finally, they review the role of small molecule inhibitors and small interfering RNAs (siRNAs) in targeting LDH activity, in addition to highlight the blocking of the lactate exchange between tumor and stroma as a novel therapeutic approach. On the other hand, Turdo et al [ 9 ] review the complex interactions between cancer stem cells (CSC), a subpopulation of cells mainly responsible of the resistance to anti-cancer therapies, and the TME. After providing a complete outline of the metabolic phenotypes shown by CSCs in various cancer models, the authors emphasize the influence of the microenvironment in CSC metabolism (with special accent on cancer-associated fibroblast, CAFs) and conclude with a list of the main therapeutic targets of CSCs.…”