Urea dysfunctions in the liver may signal 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.”

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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.”

Diets ‘devoid of vegetable matter’ may cause colon cancer

A new study emphasizes the importance to gut health of eating plenty of vegetables such as cabbage, broccoli, and kale.
selection of greens
Eating brassicas such as collards, kale, and broccoli may protect against colon cancer.
Researchers from the Francis Crick Institute in London, United Kingdom, found that keeping mice on a diet rich in a compound known as indole-3-carbinol (I3C) — which comes from such vegetables — prevented the animals’ intestines from becoming inflamed and developing colon cancer.

They report the study in a paper now published in the journal Immunity.

“Seeing the profound effect,” says study senior author Dr. Brigitta Stockinger, a group leader at the Francis Crick Institute, “of diet on gut inflammation and colon cancer was very striking.”

Our digestive system produces I3C when we eat vegetables from a “large and diverse group” of plants known as brassicas.

Brassicas include, but are not limited to: broccoli, cabbage, collards, Brussels sprouts, cauliflower, kale, kohlrabi, swede, turnip, bok choi, and mizuna.

Colon cancer typically starts as a growth, or polyp, in the lining of the colon or large intestine. It can take many years for the cancer to develop from a polyp and not all polyps become cancerous.

Cancer of the colon or rectum is the third most commonly diagnosed in both women and men in the United States, not counting skin cancer.

The American Cancer Society (ACS) estimate that there will be 97,220 new cases of diagnosed colon cancer in the U.S. in 2018.

‘Concrete evidence’ of hidden mechanism
Despite a lot of evidence about the benefits to our digestive system of a diet rich in vegetables, much of the underlying cell biology remains unknown.

The new findings are the first to give “concrete evidence” of how dietary I3C — through its effect on a cell protein known as aryl hydrocarbon receptor (AhR) — protects the gut from inflammation and cancer.

AhR has several roles, and for it to work properly, it has to be activated by a compound that binds to it uniquely. I3C is such a compound.

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One of AhR’s jobs in the gut is to pick up environmental signals and pass them on to immune cells and other cells in the lining. These signals are important for protecting the digestive tract from inflammation-promoting signals that come from the “trillions of bacteria” that live in it.

Another important role that AhR plays is helping stem cells convert into specialized gut lining cells that produce protective mucus and help extract nutrients from food.

When AhR is absent or does not work properly, the stem cells do not convert into working cells in the gut lining but “divide uncontrollably.” Uncontrolled cell division may lead to abnormal growths that can become malignant, or cancerous.

Importance of ‘plant matter’ in diet
Dr. Stockinger and her colleagues saw that normal laboratory mice that ate “purified control diets” developed colon tumors within 10 weeks, while those that ate standard “chow” containing grains and other ingredients did not develop any.

Purified control diets are tightly controlled to include precise amounts of protein, fat, carbohydrate, fiber, minerals, and vitamins. They are designed to exactly match nutritional requirements without including germs, allergens, and other substances that might introduce spurious variables in experiments.

The new study suggests that because purified control diets contain less plant matter, they have fewer compounds that activate AhR, compared with standard chow diets or diets enriched with I3C.

Dr. Chris Schiering, of Imperial College London, remarks that “even without genetic risk factors,” it would seem that “a diet devoid of vegetable matter can lead to colon cancer.”

‘Significantly fewer tumors’
The researchers used mice and organoids, or “mini guts,” grown from mouse stem cells, in their experiments. These revealed that the ability of intestinal epithelial cells to replenish themselves and repair the gut lining after infection or chemical damage was “profoundly influenced” by AhR.

The team also found that genetically engineered mice whose intestinal epithelial cells had no AhR — or could not activate the protein — failed to control an infection from a gut bacterium called Citrobacter rodentium. The animals developed gut inflammation and then colon cancer.

“However, when we fed them a diet enriched with I3C, they did not develop inflammation or cancer,” remarks first author Dr. Amina Metidji, also of the Francis Crick Institute.

Additionally, notes Dr. Metidji, when they switched mice that were already developing colon cancer to a diet rich in I3C, they found that those animals developed “significantly fewer tumors” and that those tumors were less likely to be malignant.

In discussing their results, the researchers raise the issue of whether it is the high fat content or the low consumption of vegetables in high-fat diets that explains the link to colon cancer.

The scientists now expect to continue the work on I3C and AhR with organoids grown from human gut tissue extracted in biopsies. Eventually, they expect the work to lead to human trials.

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