Urea dysfunctions in the liver may signal cancer

The urea cycle is the main way that the human body disposes of nitrogen waste. New research suggests that disruptions in this process may be an early sign of cancer.

A new study, now published in the journal Cell, suggests that the way in which the human body processes nitrogen may be key to finding new ways of detecting and destroying cancer.

Nitrogen is a gas that is vital for all organisms. Both plants and animals need it in order to make proteins.

When our body processes nitrogen, it generates a substance called urea as waste; the body later eliminates this substance through urine.

This metabolizing process is called the urea cycle, and it takes place in the liver.

New research suggests that dysregulations in the urea cycle could be a marker of cancer. The new study was led by Dr. Ayelet Erez, from the Weizmann Institute of Science in Rehovot, Israel.

Studying urea dysregulations and tumors

Dr. Erez and colleagues altered the genetic expression of urea cycle enzymes in the colon cancer tumors of rodents and compared their urea levels with those of control mice.

The mice whose urea cycle had been interfered with had lower blood levels of urea and higher levels of a substance called pyrimidine in their urine.

The scientists also examined the medical records of 100 children who had been diagnosed with cancer at the Tel Aviv Sourasky Medical Center.

"We found that on the day of their admission to the hospital," explains the lead researcher, "children with cancer had significantly decreased urea levels in their blood, compared with documented levels of urea in healthy children of the same age."

Finally, the researchers also analyzed large genomic sets in search of DNA mutations that could indicate disruptions in the urea cycle.

They found mutations in DNA, RNA, and proteins, which indicates an excess of pyrimidine. This is produced through the synthesis of nitrogen and can, in turn, promote the growth of cancer cells.

Overall, the findings suggest that dysfunctions in the urea cycle may be a good indicator of cancer.

"Standard laboratory tests check for high levels of urea in blood, but we are now showing that low levels can also signal a problem," says Dr. Erez. "Cancerous cells don't waste anything, they make use of as much nitrogen as possible instead of disposing of it in the form of urea, as do normal cells."

Making tumors vulnerable to immunotherapy

As the researchers explain, high levels of pyrimidine represent both good news and bad. The bad news is that it could make the cancer spread faster and more aggressively, but the good news is that the mutations that are related to excessive pyrimidine could make cancer cells more vulnerable to an attack from the immune system.

Therefore, malignancies characterized by a dysregulated urea cycle could be destroyed more easily with immunotherapy.

To test this hypothesis, Dr. Erez and colleagues examined melanoma tumors and found that the tumors that had dysregulated urea cycles responded better to immunotherapy. Dr. Erez and colleagues conclude:

"Taken together, our findings demonstrate that [urea cycle dysregulation] is a common feature of tumors that profoundly affects carcinogenesis, mutagenesis, and immunotherapy response."

Moreover, say the researchers, the results could lead to better tools not only for diagnosing cancer, but also for treating it.

"Yet another possibility worth exploring," Dr. Erez says, "is whether genetic manipulation of the tumor to induce such dysregulation prior to immunotherapy can increase the therapy's effectiveness."