Oncometabolites in renal cancer: Warburg’s hypothesis re-examined

The study of cancer metabolism has evolved vastly beyond the remit of tumour proliferation and survival, with an unveiling of the ostensible role of ‘oncometabolites’ in tumorigenesis. Simply defined, oncometabolites are conventional metabolites that when aberrantly accumulated have pro-oncogenic functions. Their discovery has led us to revisit the original, dispelled Warburg hypothesis, first postulated in the 1950s, of aberrant metabolism as an aetiological determinant of cancer. As such, the identification of oncometabolites alongside their attractive utilisation in diagnostics and prognostics, as novel therapeutic targets and as biomarkers of disease, has been intensely sought after in oncology. To date, fumarate, succinate and 2-hydroxyglutarate have been characterised as bona fide oncometabolites. Renal cell carcinoma (RCC) is an established example of a cancer type with extensive metabolic reprogramming during tumour initiation and progression. With oncometabolites postulated to be rooted in the oncological origins and drivers of tumorigenesis, in combination with all three of these oncometabolites remarkably implicated in RCC, this timely review synthesises the literature to date on oncometabolites in RCC, their oncogenic mechanisms and the clinical impact oncometabolites may have in the management of RCC.