Flexibility and Adaptation of Cancer Cells in a Heterogenous Metabolic Microenvironment

Abstract

The metabolic microenvironment, comprising all soluble and insoluble nutrients and co-factors in the extracellular milieu, has a major impact on cancer cell proliferation and survival. A large body of evidence from recent studies suggests that tumor cells show a high degree of metabolic flexibility and adapt to variations in nutrient availability. Insufficient vascular networks and an imbalance of supply and demand shape the metabolic tumor microenvironment, which typically contains a lower concentration of glucose compared to normal tissues. The present review sheds light on the recent literature on adaptive responses in cancer cells to nutrient deprivation. It focuses on the utilization of alternative nutrients in anabolic metabolic pathways in cancer cells, including soluble metabolites and macromolecules and outlines the role of central metabolic enzymes conferring metabolic flexibility, like gluconeogenesis enzymes. Moreover, a conceptual framework for potential therapies targeting metabolically flexible cancer cells is presented.

Fasting improves therapeutic response in hepatocellular carcinoma through p53-dependent metabolic synergism

“…Collectively, these examples, together with our results, indicate that targeting mitochondrial metabolism can be successfully combined with strategies that curb glycolysis ( 54 ). However, pharmacologic targeting of glycolysis might elicit adverse effects on nontransformed cells ( 54 ) or provoke the emergence of cancer cells that develop resistance by switching to utilization of other metabolites or nutrients ( 55 ). The pleiotropic and systemic effects of fasting on growth pathways and on the availability of various metabolites [including, but not limited to, glucose ( 5 , 6 , 56 )], on the other hand, could squelch alternative tumorigenic pathways while being safe for nontransformed cells that have evolved coping with frequent fasting periods ( 5 ).…”

Detection of Lung Cancer via Blood Plasma and 1H-NMR Metabolomics: Validation by a Semi-Targeted and Quantitative Approach Using a Protein-Binding Competitor

“…Indeed, suggestive results, pointing to an adaptive response of gluconeogenesis within cancer cells upon glucose deprivation, were provided by Leithner et al [ 64 ]. The heterogeneous character of tumors should (always) be taken into account, as more and more evidence indicates a combined appearance of glycolysis and gluconeogenesis, with a flexible difference in flux (enhanced metabolic flexibility) rather than a complete separated character within cells [ 65 , 66 ].…”

The Marine-Derived Macrolactone Mandelalide A Is an Indirect Activator of AMPK

“…Cancer cells, like normal mammalian cells, have access to numerous signaling pathways for regulation of nutrient uptake and can adapt their metabolism to match the tumor microenvironment [ 15 , 16 ]. Furthermore, pathways for mitochondrial respiration frequently remain intact allowing OXPHOS or aerobic glycolysis to proceed if a particular nutrient source becomes limited [ 15 , 17 ]. Some cancer types also appear to be inherently more dependent on OXPHOS for production of ATP, while factors such as genetic mutation and anticancer treatments can induce upregulation of OXPHOS and dysregulation of ATP synthase subunits [ 18 , 19 ].…”