Duke University researchers have discovered a promising target for renal cell carcinomas. A study appearing in Cancer Research shows that the majority of these cancers rewire their metabolism in a way that leaves them addicted to an outside nutrient called cystine.
By depriving the cancer cells of the amino acid cystine, the researchers were able to trigger a form of cell death called necrosis in mouse models of the disease.
About three-fourths of renal cell carcinoma cases are marked by a missing VHL tumor-suppressor gene, which keeps healthy cells from developing into tumors.
Researchers decided to investigate how this single genetic change could affect the metabolism and nutrient requirement of cancer cells.
They subjected the cancer cells to a nutrient deprivation test, removing each of the 15 amino acids from their growth media, one by one. Most of the time, the cells weathered the change quite well, slowing down their growth but otherwise remaining healthy. But when cystine was removed, the cells swelled up and floated to the surface, a sure sign of necrotic death.
The researchers then conducted a number of genetic analyses to piece together the network of genes responsible for this nutrient addiction. Normally, the VHL gene acts to suppress another gene called tumor necrosis factor alpha or TNF-alpha. When VHL is lost, the high levels of TNF-alpha beget a faster-growing, more aggressive form of cancer that sheds loads of dangerous free radicals.
Cystine is responsible for maintaining high levels of antioxidants that disarm free radicals of oxygen; so when the researchers got rid of this nutrient, the cancer cells essentially died by their own hand of free radical damage.
The researchers showed that the approach was successful both in tissue culture cells as well as in mice. They implanted renal cell carcinoma tumors into mice and then treated the animals with sulfasalazine, a drug that blocks cystine uptake. They found that the treatment induced necrosis and significantly delayed tumor growth.