Metabolic abnormalities are a characteristic feature of clear cell renal cell carcinoma (ccRCC). A recent study by Celeste Simon and colleagues reports a role of altered ammonia metabolism in ccRCC progression. Ammonia is metabolized via the urea cycle, which converts free ammonia into urea.

“We have a long-standing interest in the relationship between oxygen availability, hypoxia-inducible factors, metabolism and tumour progression, and ccRCC represents an ideal platform to study this relationship,” says Simon. “Moreover, we think that finding metabolic commonalities across tumours with diverse genetic backgrounds could significantly advance treatment efforts.”

Using a combination of metabolomic, genomic and transcriptomic analyses, the researchers show that the expression of key urea cycle enzymes, including arginase 2 (ARG2) and argininosuccinate synthase 1 (ASS1), is strongly repressed in ccRCC tumours compared with healthy kidney tissue. In addition, re-expression of ARG2 or ASS1 in ccRCC xenograft models reduced tumour growth, indicating tumour-suppressive effects of these enzymes. Further analyses demonstrated that ARG2 suppresses ccRCC growth via depletion of the essential coenzyme pyridoxal 5′-phosphate and via synthesis of polyamines, resulting in accumulations to toxic levels. As ccRCC cells are arginine auxotrophs owing to loss of urea cycle enzymes, the researchers also suggest that competition with tumour-infiltrating cytotoxic T cells for circulating arginine might have immunosuppressive effects.

“Changes in urea cycle enzymes in ccRCC protect a critical biosynthetic cofactor, avoid a toxic build-up of polyamines and potentially provide an immunosuppressive microenvironment,” concludes Simon. “We now plan to determine if competition for arginine does indeed affect infiltrating cytotoxic T cells and if there is a way to re-express urea cycle enzymes in ccRCC using epigenetic modifiers.”