Brief Report: An Evolutionary Basis to Cancer Growth

Abstract Background. Recently we have reviewed the evidence that excessive intake of fructose, present in added sugars, may be a unique nutrient that stimulates tumor growth while also causing obesity and metabolic syndrome, thereby providing one of the reasons why obesity is associated with increased risk for various cancers. Prior studies have suggested that one of the reasons fructose increases the risk for cancer may be due in part to its metabolite uric acid, and both a meta-analysis and Mendelian randomization study confirm uric acid is a risk factor. Here we suggest that a mutation in uric acid metabolism may have provided survival advantage to our ancestors but ironically increase our risk for cancer today.Methods. Ancestral humans lost the gene uricase during the mid-Miocene where it led to higher uric acid levels that facilitated the effects of fructose to stimulate fat accumulation. Here we tested whether a loss of uricase would also facilitate tumor growth. Experiments were performed in mice in which uricase was inactivated by either knocking out the gene or by inhibiting uricase with oxonic acid. We also studied mice transgenic for uricase. These mice were injected with breast cancer cells and followed for 4 weeks.Results. The inhibition or knockout of uricase was associated with a remarkable increase in tumor growth and metastases. In contrast, transgenic uricase mice showed reduced tumor growth.Conclusion. A loss of uricase increases the risk for tumor growth. Prior studies have shown that the loss of the mutation facilitated the ability of fructose to increase fat which provided a survival advantage for our ancestors that came close to extinction from starvation in the mid Miocene. Today, however, excessive fructose intake is rampant and increasing our risk not only for obesity and metabolic syndrome, but also cancer. Obesity-associated cancer may be due, in part, to a mutation 15 million years ago that acted as a thrifty gene.