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.

Keywords: adaptability; cancer; gluconeogenesis; heterogeneity; metabolic microenvironment.

Figure 1

Heterogenous perfusion and nutrient supply in solid cancers. Typical pattern observed in scans of perfusion magnetic resonance imaging, showing regions of high (red) and low blood perfusion (white) scattered around solid cancers. The vascular network, comprising tumor arteries (red), veins (blue) and the connecting microvessels, is frequently chaotic, resulting in fluctuating, insufficient blood flow. On a microscopic scale, steep gradients for nutrients and oxygen with increasing distance from the capillaries occur (detail).

Figure 2

Biosynthetic pathways branching from glycolysis in glucose-replete conditions. Glucose is the main precursor for glycolysis (blue arrows). Glycolytic enzymes are upregulated in many cancer types, leading to enhanced generation of glycolytic intermediates. These serve as precursors for numerous metabolic pathways (marked in red) necessary for the biosynthesis of cellular biomass (highlighted in grey). Excess glycolytic intermediates are converted to pyruvate and finally lactate, which is released. The conversion of pyruvate to acetyl-CoA, leading to full oxidation in mitochondria, is relatively decreased. Additionally, amino acid catabolism, primarily glutaminolysis, is required to meet the cancer cell’s demand for nitrogen and biosynthetic precursors. PPP, pentose phosphate pathway; HK2, hexokinase 2; PFK, phosphofructokinase; PKM2, pyruvate kinase M2; LDHA, lactate dehydrogenase A; GLS, glutaminase; TCA cycle, tricarboxylic acid cycle.

Figure 3

Gluconeogenesis and other rescue pathways for the generation of metabolic intermediates in low-glucose conditions. Precursors for biomass biosynthesis are produced from multiple alternative nutrients, like lactate or amino acids or from degradation of macromolecules (via autophagy or macropinocytosis, brown arrows/box) during a lack of glucose. Initial steps of the gluconeogenesis pathway (orange arrows), mediated by PCK1 or PCK2, are key for the generation of glycolytic intermediates under low-glucose conditions. These may serve as precursors for different metabolic pathways (marked in red) necessary for the biosynthesis of cellular biomass (highlighted in grey) also in the absence of glucose.Furthermore, the TCA cycle and enzymes of pyruvate carboxylation and degradation play an important role in the degradation or interconversion of alternative, noncarbohydrate precursors/nutrients according to the cell’s demands. TCA cycle, tricarboxylic acid cycle, Krebs cycle; PCK1/2, phosphoenolpyruvate carboxykinase cytoplasmic isoform (PCK1) or mitochondrial isoform (PCK2); FBP1/2, fructose-1,6-bisphosphatase 1; PPP, pentose phosphate pathway.

Figure 4

Targeting aberrant cancer metabolism and metabolic flexibility as an anticancer strategy. As an example of cancer cell metabolic flexibility, cancer cells (represented as circles) may switch from a state of high glucose consumption/glycolysis (brown circles) to the use of alternative nutrients (e.g., lactate; symbolized by red circles) according to the availability in the tumor microenvironment or in response to other factors. Green circles in the right upper quadrant represent cells consuming abundant glucose and “alternative” nutrients simultaneously. Treatments targeting metabolic pathways in cancer cells, like glycolysis, should take metabolic flexibility into account. Inhibition of multiple, compensatory metabolic pathways simultaneously might be necessary to reduce proliferation (light grey) or induce cell death (dark grey).