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Review
. 2016 Apr;73(7):1333-48.
doi: 10.1007/s00018-015-2098-5. Epub 2015 Dec 1.

Metabolic changes associated with tumor metastasis, part 1: tumor pH, glycolysis and the pentose phosphate pathway

Valéry L Payen  1 , Paolo E Porporato  1 , Bjorn Baselet  1   2 , Pierre Sonveaux  3
Affiliations
Review

Metabolic changes associated with tumor metastasis, part 1: tumor pH, glycolysis and the pentose phosphate pathway

Valéry L Payen et al. Cell Mol Life Sci. 2016 Apr.

Abstract

Metabolic adaptations are intimately associated with changes in cell behavior. Cancers are characterized by a high metabolic plasticity resulting from mutations and the selection of metabolic phenotypes conferring growth and invasive advantages. While metabolic plasticity allows cancer cells to cope with various microenvironmental situations that can be encountered in a primary tumor, there is increasing evidence that metabolism is also a major driver of cancer metastasis. Rather than a general switch promoting metastasis as a whole, a succession of metabolic adaptations is more likely needed to promote different steps of the metastatic process. This review addresses the contribution of pH, glycolysis and the pentose phosphate pathway, and a companion paper summarizes current knowledge regarding the contribution of mitochondria, lipids and amino acid metabolism. Extracellular acidification, intracellular alkalinization, the glycolytic enzyme phosphoglucose isomerase acting as an autocrine cytokine, lactate and the pentose phosphate pathway are emerging as important factors controlling cancer metastasis.

Keywords: Glycolysis; Lactate; Pentose phosphate pathway (PPP); Phosphoglucose isomerase (PGI); Tumor metastasis; Tumor pH.

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Figures

Fig. 1
Fig. 1
Model depicting potential metabolic changes associated to cancer metastasis. Tumors are composed of malignant and host cells that are highly heterogeneous metabolically. According to the model, metastatic progenitor cells could evolve from glycolytic tumor cells in the glycolytic compartment of a primary tumor where a low extracellular pH (pHe), lactate and other microenvironmental parameters trigger tumor cell migration and invasion. On their metastatic route, tumor cells would acquire different metabolic features comprising, e.g., increased pentose phosphate pathway activity and an enhanced production of mitochondrial reactive oxygen species further promoting migration and invasion, facilitating intravasation, survival in the blood stream and extravasation, and conferring stem cell capabilities to metastatic progenitor cells. At the secondary site in a distant organ such as the lungs, metastatic progenitor cells would revert to a more glycolytic phenotype associated with cell proliferation (the Warburg effect) and metastasis formation. Of note, according to the model, metastatic progenitor cells would constitute a distinct population/populations of cells among all circulating tumor cells
Fig. 2
Fig. 2
Simplified scheme highlighting the contribution of tumor pH, glycolysis and the pentose phosphate pathway to tumor metastasis. Enzymes are represented in italicized blue font and their substrates in bold black. Tumor cells avidly take up glucose, which is progressively broken down during glycolysis to form pyruvate, a metabolite that fuels the tricarboxylic acid (TCA) cycle. Pyruvate can also be converted to lactate during lactate fermentation, and lactate is released from the cell along with protons, inducing intracellular alkalinization and extracellular acidification. This process and other ion exchangers involved in cellular pH regulation promote tumor cell migration and metastasis (shown in the migrating tumor cell on top right). Lactate and a low extracellular pH (pHe) can also promote tumor angiogenesis by activating several signaling pathways represented in the endothelial cell shown on bottom right. The glycolytic enzyme phosphoglucose isomerase acts as an autocrine signaling factor that triggers the epithelial-to-mesenchymal transition (EMT), migration, invasion and angiogenesis. The pentose phosphate pathway promotes tumor cell survival upon detachment. Other abbreviations: AE2 anion exchanger 2, AP1 activator protein 1, bFGF basic fibroblast growth factor, CA IX carbonic anhydrase IX, GLUT glucose transporter, IL8 interleukin 8, MCT monocarboxylate transporter, NBC1 sodium bicarbonate cotransporter 1, NF-κB nuclear factor-κB, NHE-1 sodium-proton exchanger-1, pHi intracellular pH, VEGF-A vascular endothelial growth factor-A
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