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Metabolic alterations in hereditary and sporadic renal cell carcinoma

Nature Reviews Nephrology volume 20, pages 233–250 (2024)Cite this article

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Abstract

Kidney cancer is the seventh leading cause of cancer in the world, and its incidence is on the rise. Renal cell carcinoma (RCC) is the most common form and is a heterogeneous disease comprising three major subtypes that vary in their histology, clinical course and driver mutations. These subtypes include clear cell RCC, papillary RCC and chromophobe RCC. Molecular analyses of hereditary and sporadic forms of RCC have revealed that this complex and deadly disease is characterized by metabolic pathway alterations in cancer cells that lead to deregulated oxygen and nutrient sensing, as well as impaired tricarboxylic acid cycle activity. These metabolic changes facilitate tumour growth and survival. Specifically, studies of the metabolic features of RCC have led to the discovery of oncometabolites — fumarate and succinate — that can promote tumorigenesis, moonlighting functions of enzymes, and substrate auxotrophy owing to the disruption of pathways that enable the production of arginine and cholesterol. These metabolic alterations within RCC can be exploited to identify new therapeutic targets and interventions, in combination with novel approaches that minimize the systemic toxicity of metabolic inhibitors and reduce the risk of drug resistance owing to metabolic plasticity.

Key points

  • Renal cell carcinoma (RCC) is a metabolic disease that develops from mutations in genes essential for cellular metabolism.

  • Metabolic alterations and adaptations allow cancer cells to proliferate, survive nutrient depletion and hypoxia, as well as promoting immune evasion, metastasis and resistance to therapy.

  • Hereditary RCC syndromes have demonstrated how perturbations in nutrient and oxygen sensing pathways, and the tricarboxylic acid cycle drive RCC tumorigenesis.

  • Sporadic RCC subtypes have both unique and shared metabolic alterations that promote cancer progression.

  • A lack of preclinical models for non-clear cell RCC tumours has limited the study of these important diseases.

  • Clarification of RCC-associated metabolic alterations can provide novel therapeutic targets, and metabolic interventions for RCC are currently in development.

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Fig. 1: Metabolic pathways in hereditary RCC.
Fig. 2: Glucose metabolism in ccRCC.
Fig. 3: Mitochondrial metabolism in ccRCC.
Fig. 4: Cholesterol and tryptophan metabolism in ccRCC.

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Acknowledgements

M.C.S. is supported by P30CA016520, R35CA220483 and R01CA276512 from the NIH. N.J.C. is supported by F30CA271654 from the NIH.

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  1. Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Nathan J. Coffey & M. Celeste Simon

  2. Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, USA

    M. Celeste Simon

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A cell that has more than one mitochondrial genome.

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Coffey, N.J., Simon, M.C. Metabolic alterations in hereditary and sporadic renal cell carcinoma. Nat Rev Nephrol 20, 233–250 (2024). https://doi.org/10.1038/s41581-023-00800-2

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