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.
Highlights
This corresponds to a lower average concentration of glucose in the tumor extracellular this study, the extracellular fluid was sampled by rapid centrifugation of fresh cancer tisfluid, as foundcontrolling in a recent a murine pancreatic cancer model
Glutamine and lactate represent important alternative fuels, their use in cancer cells is not limited to conditions of glucose deprivation
Given their central position in carbon metabolism, regulating the OAA-PEP-pyruvate node, PCK1 or PCK2 might play an important role in modulating metabolism and cell fate decisions in many different cancer types, especially in a glucose-poor microenvironment
Summary
It is largely determined by the blood supply, tumor cells and non-neoplastic cells of the tumor microenvironment shape the metabolic landscape in the tumor due to consumption of nutrients and release of waste and other metabolites [1,2,3] These interactions between cancer cell metabolic activity and extratumoral metabolites are reminiscent of the concept of plasticity and reciprocity observed for cancer cell interaction with the extracellular matrix and non-neoplastic cells, like fibroblasts [4]. The metabolic microenvironment of solid cancers is heterogenous, comprising areas of hypoxia and nutrient scarcity due to an insufficient vascular network These conditions may impose severe stress on neoplastic tumor cells, triggering significant adaptations [3,4,7]. We discuss potential therapeutic strategies to target metabolically flexible cancer cells
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