Arginine is an amino acid produced naturally by our bodies and is abundant in the fish, meat and nuts we eat. But as recent research in Science Advances reveals, arginine is also an essential nutrient for cancer cells. And by starving them of it, tumors may become more vulnerable to the body’s natural immune response — reports Rockefeller University in New York.
Researchers at Sohail Tavazoie’s Laboratory of Systems Cancer Biology discovered that this amino acid becomes restricted in several human cancers, prompting these cells to seek a clever genetic solution: when arginine levels fall, they manipulate proteins available to them to more efficiently absorb arginine and other amino acids. And remarkably, in an effort to keep growing, they induce mutations that reduce their dependence on them.
(Bron University of Pittsburgh – 2023)
Dennis Hsu physician scientist at UPMC Hillman Cancer Center in Pittsburgh
“It’s like having a Lego set, and you’re trying to build a nice model airplane, and you’re out of proper bricks,” says first author Dennis Hsu, a former member of Tavazoie’s lab and now a physician-scientist at UPMC Hillman Cancer Center in Pittsburgh. “The only way to still build the plane would be if you changed blueprints that don’t require the missing bricks.”
The connection between arginine and cancer. At the cellular level, arginine plays a role in several processes, from nitrogen waste removal to protein synthesis. It’s also one of the few amino acids shown to regulate how immune cells respond to cancer and other types of immunological triggers, Hsu says.
For example, the deficiency is linked to the inflamed tissues of people with Crohn’s disease, ulcerative colitis, inflammatory bowel disease or an H. pylori infection, whose tissues may have low levels of arginine. If people with these conditions go untreated, they have a higher risk of developing stomach or colon cancer.
The researchers discovered the link between arginine and cancer as part of a larger study of codons, triplets of DNA bases that each contain the recipe for producing a single amino acid. Searching the Cancer Genome Atlas, Hsu documented thousands of cases of codon mutations, but one stood out among all the cancers: arginine codons, which were much more lost during mutations than they should have been. Stomach and colon cancer showed the most dramatic shortcomings. “This was a very surprising discovery that we didn’t expect,” says Tavazoie.
The researchers do not know how the first arginine drops came about. “We think that some cancers develop under low arginine conditions and carry this history in their DNA,” says Hsu. Cellular malnutrition Hsu and his co-authors spent months in the lab growing cancer cells and then starving them of arginine. As they put the cells through multiple rounds of cellular malnutrition, the cancer cells began to mutate as they tried different ways to access a renewed supply of the essential nutrition. Not all of these strategies worked. One successful method was to increase the amount of amino acid transporters so that the cells could absorb arginine and other amino acids more efficiently. But even these functional knockoffs were mostly meager resources. Meanwhile, the errors got worse as the cells replicated, resulting in changes to the genome, such as mutated genes and malformed proteins.
(Bron Wikipedia – 2023)
This cancer occurred in a 40-year-old woman who complained of abdominal pain. Endoscopically, it was a “very suspicious” ulcer in her stomach. Biopsy showed diffuse infiltrating signet ring cell adenocarcinoma
In another experiment, Hsu found an increase in the number of mutations toward codons that produce amino acids that were more abundant in the environment of the cancer cells. These suddenly became more palatable to the cancer cells, which seemed to try to make do with what they had—similar to cobble together a meal from a few random items that happen to be in your fridge. Linking a specific nutrient to a specific DNA change through this kind of so-called directed evolution “hadn’t been reported before to our knowledge,” says Tavazoie.
From red flag to bullseye. Interestingly, this ability to codon (A codon of triplet is to persuade a trio of bases (adenine, cytosine, guanine or uracil) in mRNA that carry the genetic code.) to do their bidding, could possibly lead to the cancer cells being undone. That’s because in the process of trying to keep themselves alive while malnourished, the cells accumulate so many mutations that they start looking very strange to the immune system. “You have some random, abnormal-looking proteins because of all the mutations, and those are more likely to be recognized by the immune system as something that doesn’t belong there,” says Hsu. Once deeply mutated, arginine-starved cancer cells that might have flown under the immune system’s radar may now be waving a torn red flag at them.
The findings have potential implications for immunotherapy. “By starving a cancer cell, you may be able to promote the acquisition of new mutations that can then be recognized by the immune system,” says Hsu. “We haven’t tested this, but it would be really cool to try.”