Oncometabolites in renal cancer

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.