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.
Highlights
IntroductionDespite significant advances in cancer prevention and treatment, metastatic disease is mostly incurable and resistant to common therapeutics
Despite significant advances in cancer prevention and treatment, metastatic disease is mostly incurable and resistant to common therapeutics.The development of cancer depends on a small pool of tumor cells owing a phenotype comparable to normal adult stem cells, called cancer stem cells (CSCs), which are characterized by self-renewal and multilineage differentiation capabilities, as well as a great ability to initiate and promote tumorigenesis, metastasis formation and anticancer therapy resistance [1]
In metastatic breast cancer, extracellular vesicles released by cancer-associated fibroblasts (CAFs) contain mitochondrial DNA that is internalized by CSCs and used to sustain oxidative phosphorylation (OXPHOS) and exit from quiescence induced by hormonal therapy [206]
Summary
Despite significant advances in cancer prevention and treatment, metastatic disease is mostly incurable and resistant to common therapeutics. Cancer cells are not characterized by a unique metabolic profile Both intrinsic and extrinsic factors, such as a nutrient-poor microenvironment, have critical roles in determining cell metabolic phenotypes. One conceivable mechanism of interchange between neoplastic and stromal cells is represented by the release of miRNAs and exosomes, small particles containing nucleic acids (DNA, mRNA and miRNA), metabolites and inflammatory factors [8] Exosomes and their cargo are in charge for the establishment of the pre-metastatic niche and, importantly, may contribute to cancer treatment failure [9,10]. The ‘Warburg effect’ foresees the conversion of pyruvate to lactate, from glucose, under aerobic conditions with a consequent predominance of glycolysis on OXPHOS [12] This metabolic reprogramming has been initially ascribed to defects on mitochondrial function [13]. In this context an enhanced nucleotide production, as it is the case in cancer cells, leads to a decrease in the NAD+/NADH ratio, which in turn encourages the conversion of glucose to lactate [19]
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