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Choline metabolism in malignant transformation

Key Points

  • Some of the levels of metabolic intermediates that are generated in choline phospholipid metabolism, particularly phosphocholine (PCho) and total choline (tCho), are elevated in cancer, and can be used for non-invasive detection in cancer diagnosis and staging by using magnetic resonance spectroscopy (MRS) or positron emission tomography (PET).

  • Several enzymes in choline metabolism, such as choline transporter-like protein 1 (CTL1), choline kinase-α (CHKα), CTP:phosphocholine cytidylyltransferase (CCT), phosphatidylcholine-specific phospholipase D (PC-PLD) and PC-PLC, are overexpressed and/or activated in cancer and can potentially be used as prognostic markers.

  • Overexpression and activation of choline cycle enzymes are mediated by oncogenic signalling via pathways such as the RAS and PI3K–AKT pathways, and by transcription factors associated with oncogenesis such as hypoxia-inducible factor 1 (HIF1). Recent studies point to a reciprocal interaction between choline cycle enzymes and oncogenic signalling, where modulation of the enzymes can contribute to enhancing oncogenic signalling.

  • The therapeutic response of tumours can be monitored non-invasively by MRS of the tCho signal because treatment with conventional chemotherapeutic agents results in a decrease of tCho levels in responding, but not in non-responding, tumours.

  • Inhibition of oncogenic signalling pathways with targeted anticancer drugs results in altered choline-containing metabolite levels. Therefore, these metabolites could provide downstream metabolic readouts of the effective inhibition of these pathways.

  • New molecularly targeted therapeutic opportunities arise from targeting choline cycle enzymes such as CHKα, which is currently being tested in Phase I clinical trials.

Abstract

Abnormal choline metabolism is emerging as a metabolic hallmark that is associated with oncogenesis and tumour progression. Following transformation, the modulation of enzymes that control anabolic and catabolic pathways causes increased levels of choline-containing precursors and breakdown products of membrane phospholipids. These increased levels are associated with proliferation, and recent studies emphasize the complex reciprocal interactions between oncogenic signalling and choline metabolism. Because choline-containing compounds are detected by non-invasive magnetic resonance spectroscopy (MRS), increased levels of these compounds provide a non-invasive biomarker of transformation, staging and response to therapy. Furthermore, enzymes of choline metabolism, such as choline kinase, present novel targets for image-guided cancer therapy.

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Figure 1: Overview of deregulated choline metabolism in cancer.
Figure 2: Control of choline metabolism by oncogenic signalling pathways.
Figure 3: The major enzymes involved in choline phospholipid metabolism in the cell.

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Acknowledgements

The authors gratefully acknowledge useful discussions with F. Podo, R. Gillies, H. Degani and J. Delikatny. The authors apologize for only including a limited number of studies owing to journal restrictions for the number of citations. Support from P50 CA103175, P30 CA006973, R01 CA73850, R01 CA82337, R01 CA136576, R01 CA138515, R01 CA138264, R01 CA134695, R01 CA154725, R21 CA120010, RO1 CA130819 and P50 CA097257 is gratefully acknowledged.

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Correspondence to Kristine Glunde, Zaver M. Bhujwalla or Sabrina M. Ronen.

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Glossary

Total choline-containing compounds

(tCho). The sum of choline (Cho), phosphocholine (PCho) and glycerophosphocholine (GPC), this term was coined because these three metabolite signals appear as one overlapping signal in non-invasive in vivo1H magnetic resonance spectra owing to limited spectral resolution.

Magnetic resonance spectroscopy

(MRS). A technique that measures the nuclear magnetic resonance of 1H, 31P and other magnetic resonance-active nuclei to determine their physical and chemical properties either non-invasively in live organisms or at high spectral resolution in ex vivo samples.

Phosphomonoesters

(PMEs). Phospholipid metabolism intermediates, such as phosphocholine (PCho) and phosphoethanolamine (PEtn), which contain one ester bond between the phosphate group and the specific phospholipid head group alcohol.

Phosphodiesters

(PDEs). Phospholipid metabolism intermediates, such as glycerophosphocholine (GPC) and glycerophosphoethanolamine (GPE), which contain two ester bonds at the phosphate group, one to the specific phospholipid head group alcohol and a second one to glycerol.

Magic angle spinning

(MAS). A specialized magnetic resonance spectroscopy technique that avoids tissue extraction to detect high-resolution spectra by spinning solid tissue samples at the angle of 54.74° with respect to the magnetic field. These tissue samples can be used for subsequent histological, biochemical and genetic analyses.

Phorbol esters

A class of compounds originally derived from esterification of the plant compound phorbol, which promote tumorigenesis through the activation of protein kinase C.

MRS imaging

(MRSI). Applies magnetic resonance spectroscopy (MRS) in a spatially resolved manner, thereby providing metabolite concentrations in tissue in two or three spatial dimensions and allowing for the display of metabolic maps throughout the tissue.

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Glunde, K., Bhujwalla, Z. & Ronen, S. Choline metabolism in malignant transformation. Nat Rev Cancer 11, 835–848 (2011). https://doi.org/10.1038/nrc3162

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