Oncometabolites in renal cancer

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Abstract

The study of cancer metabolism has evolved vastly beyond the remit of tumour proliferation and survival with the identification of the role of ‘oncometabolites’ in tumorigenesis. Simply defined, oncometabolites are conventional metabolites that, when aberrantly accumulated, have pro-oncogenic functions. Their discovery has led researchers to revisit the Warburg hypothesis, first postulated in the 1950s, of aberrant metabolism as an aetiological determinant of cancer. As such, the identification of oncometabolites and their utilization in diagnostics and prognostics, as novel therapeutic targets and as biomarkers of disease, are areas of considerable interest in oncology. To date, fumarate, succinate, l-2-hydroxyglutarate (l-2-HG) and d-2-hydroxyglutarate (d-2-HG) have been characterized as bona fide oncometabolites. Extensive metabolic reprogramming occurs during tumour initiation and progression in renal cell carcinoma (RCC) and three oncometabolites — fumarate, succinate and l-2-HG — have been implicated in this disease process. All of these oncometabolites inhibit a superfamily of enzymes known as α-ketoglutarate-dependent dioxygenases, leading to epigenetic dysregulation and induction of pseudohypoxic phenotypes, and also have specific pro-oncogenic capabilities. Oncometabolites could potentially be exploited for the development of novel targeted therapies and as biomarkers of disease.

Key points

  • Oncometabolites are aberrantly accumulated metabolites that possess pro-oncogenic capabilities, they contribute to tumorigenesis via epigenetic dysregulation and can influence tumour progression through phenotypic switches such as epithelial to mesenchymal transition.

  • l-2-hydroxyglutarate, fumarate and succinate are bona fide renal cell carcinoma (RCC) oncometabolites; exploitation of these oncometabolites and their downstream signalling effects are attractive targets for novel therapies and as biomarkers of disease.

  • Oncometabolites have shared pro-oncogenic functions owing to their ability to inhibit α-ketoglutarate-dependent dioxygenases as well as individual oncometabolite-specific functions.

  • Chromatin remodelling via oncometabolites may recapitulate the effects of other epigenetic modifiers mutated in RCC, thus converging on the same gene signature; identification of the underlying pathways influences treatment strategy.

  • Elucidation of exogenous factors that give rise to oncometabolite production, such as hyperglycaemia, may prove to be a synergistic strategy to reduce the levels of oncometabolites and their subsequent sequelae.

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Fig. 1: Key metabolic pathways in renal cell carcinoma.
Fig. 2: Individual and shared oncometabolite signalling pathways.
Fig. 3: Strategies for targeting oncometabolite-associated pathways.

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Acknowledgements

C.Y. is funded by the Wellcome Trust and The Urology Foundation. C.F. is supported by the Medical Research Council, grant MRC_MC_UU_12022/6.

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C.Y. C.F. and G.D.S. researched the data for the article and made substantial contributions to discussions of the content. C.Y. wrote the manuscript. C.Y. G.D.S. and C.F. reviewed and edited the manuscript before submission.

Correspondence to Grant D. Stewart or Christian Frezza.

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C.Y. declares no competing interests. G.D.S. has received educational grants from Pfizer, AstraZeneca and Intuitive Surgical, consultancy fees from Merck, Pfizer, EUSA Pharma and CMR Surgical, travel expenses from Pfizer and speaker fees from Pfizer. C.F. is an adviser of Istesso Limited and a member of the Scientific Advisory Board of Owlstone Medical.

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Nature Reviews Nephrology thanks J. Bedke, R. Deberardinis, J. Hsieh and R. Weiss for their contribution to the peer review of this work.

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Glossary

Hereditary leiomyomatosis and renal cell cancer

(HLRCC). An autosomal dominant hereditary cancer syndrome caused by germline mutations in FH. HLRCC is characterized by cutaneous and uterine leiomyomas and is associated with papillary type 2 RCC.

Hereditary paraganglioma

(PGL). A dominantly inherited rare condition consisting of benign tumours arising from neuroendocrine tissues, typically in the head and neck.

Phaeochromocytomas

(PCCs). A type of paraganglioma that arises from the adrenal glands and produces catecholamines such as adrenaline.

Pseudohypoxic phenotype

Hypoxic-like metabolic changes that are observed in cells in the absence of a hypoxic environment or stimulant.

Neomorphic

A novel and/or non-canonical function of an enzyme.

Heterozygous germline mutations

Inheritance of one copy of a mutant allele and one copy of the wild type allele.

Loss of heterozygosity

(LOH). The loss of one allele of a genetic locus.

CpG islands

Clusters of dinucleotide sequence of a cytosine followed by a guanosine nucleotide in the 5′–3′ direction. CpG islands are often found in promoter regions upstream of transcription sites.

Half maximal inhibitory concentration

(IC50). A measure of the potency of a substance to inhibit a specific biological process or function by 50%.

Anaplerosis

The process of replenishing the tricarboxylic acid cycle intermediates that have been extracted for biosynthesis.

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Yong, C., Stewart, G.D. & Frezza, C. Oncometabolites in renal cancer. Nat Rev Nephrol (2019) doi:10.1038/s41581-019-0210-z

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