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Metabolic reprogramming in clear cell renal cell carcinoma

Nature Reviews Nephrology volume 13, pages 410–419 (2017)Cite this article

Subjects

Key Points

  • The incidence of kidney cancer, particularly clear cell renal cell carcinoma, is increasing and knowledge of its pathophysiology is essential for nephrologists

  • Reprogramming of metabolic pathways enables cancer cells to rapidly proliferate, survive in conditions of nutrient depletion and hypoxia, and evade the immune system

  • Most forms of kidney cancer are associated with reprogramming of metabolic pathways including oxygen sensing, the tricarboxylic acid cycle and the metabolism of tryptophan, fatty acids, glucose, glutamine and arginine

  • Metabolic reprogramming provides opportunities for functional imaging approaches based on the altered pathways

  • Novel therapies for kidney cancers that target critical proteins or enzymes that are involved in dysregulated metabolic pathways are being developed

Abstract

Research in many cancers has uncovered changes in metabolic pathways that control tumour energetics and biosynthesis, so-called metabolic reprogramming. Studies in clear cell renal cell carcinoma (ccRCC) have been particularly revealing, leading to the concept that ccRCC is a metabolic disease. ccRCC is generally accompanied by reprogramming of glucose and fatty acid metabolism and of the tricarboxylic acid cycle. Metabolism of tryptophan, arginine and glutamine is also reprogrammed in many ccRCCs, and these changes provide opportunities for new therapeutic strategies, biomarkers and imaging modalities. In particular, metabolic reprogramming facilitates the identification of novel and repurposed drugs that could potentially be used to treat ccRCC, which when metastatic has currently limited long-term treatment options. Further research and dissemination of these concepts to nephrologists and oncologists will lead to clinical trials of therapeutics specifically targeted to tumour metabolism, rather than generally toxic to all proliferating cells. Such novel agents are highly likely to be more effective and to have far fewer adverse effects than existing drugs.

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Figure 1: Metabolic reprogramming in clear cell renal cell carcinoma (ccRCC).
Figure 2: Altered tryptophan metabolism in clear cell renal cell carcinoma (ccRCC).
Figure 3: Altered energy and glutamine metabolism in clear cell renal cell carcinoma (ccRCC).
Figure 4: Altered arginine metabolism in clear cell renal cell carcinoma (ccRCC).

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Acknowledgements

All authors researched the data for the article, made substantial contributions to discussions of the content, wrote the article and reviewed or edited the manuscript before submission.

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Authors and Affiliations

  1. University of California, San Diego, Sanford Consortium for Regenerative Medicine, Room 4810, 2880 Torrey Pines Scenic Drive, La Jolla, 92037–0695, California, USA

    Hiromi I. Wettersten

  2. Division of Nephrology, University of California Davis, Genome and Biomedical Sciences Facility, Room 6311, 451 Health Sciences Drive, Davis, 95616, California, USA

    Omran Abu Aboud & Robert H. Weiss

  3. University of California Davis Comprehensive Cancer Center, 4501 X Street, Suite 3003, Sacramento, 95817, California, USA

    Primo N. Lara Jr

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  1. Hiromi I. Wettersten
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  2. Omran Abu Aboud
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  3. Primo N. Lara Jr
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  4. Robert H. Weiss
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Correspondence to Robert H. Weiss.

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Tricarboxylic acid (TCA) cycle

A series of chemical reactions that comprises the oxidation of acetyl-CoA to release stored energy.

Warburg effect

The phenomenon of cells producing energy primarily by glycolysis followed by lactate fermentation, rather than by glycolysis followed by the tricarboxylic acid (TCA) cycle in mitochondria.

Oncometabolite

A small molecule component of normal metabolism that on accumulation, results in metabolic dysregulation and consequently primes cells for progression to malignancy.

Semi-essential amino acid

An amino acid that can only be synthesized under specific metabolic conditions. Also known as a conditionally essential amino acid.

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Wettersten, H., Aboud, O., Lara, P. et al. Metabolic reprogramming in clear cell renal cell carcinoma. Nat Rev Nephrol 13, 410–419 (2017). https://doi.org/10.1038/nrneph.2017.59

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