- Colorectal cancer is the third most common type of cancer and the second most common cause of cancer death in the world.
- Researchers from the University of Michigan Medical School discovered high levels of ammonia in colon cancer tumors can keep them from responding to immunotherapy.
- Scientists found they can lower ammonia levels by using drugs for hyperammonemia, making them more sensitive to treatment.
Colorectal cancer — also known as bowel or colon cancer — is the third most common type of cancer and the second most common cause of cancer death around the world.
There is currently no cure for colorectal cancer. Treatment options include surgery, chemotherapy, immunotherapy, radiation therapy, or a colectomy.
Now, researchers from the University of Michigan Medical School have found high levels of ammonia in colon tumors keep them from responding well to immunotherapy.
They say using the FDA-approved drug hyperammonemia helps reduce the tumor’s ammonia levels, making it more sensitive to treatment.
The study was recently published in the journal Cell Metabolism.
Ammonia and colon cancer
Ammonia is one of the body’s naturally occurring waste products.
The body makes ammonia during the digestion process, which is then moved to the liver where it is turned into urea and removed from the body during urination.
Why do colorectal tumors have a high level of ammonia in the first place — is that something normal?
Yes, said Dr. Anton Bilchik, a surgical oncologist and division chair of general surgery at Providence Saint John’s Health Center and chief of medicine and Director of the Gastrointestinal and Hepatobiliary Program at Saint John’s Cancer Institute in California who was not involved in the study.
“Our body has 2 trillion bacteria called the microbiome,” he explained to Medical News Today. “The thought is that there’s some disruption in the bacteria in patients with colon cancer that leads to the breakdown of certain products that increase the amount of ammonia in colon cancer cells.”
“In colon cancer, there appears to be a disproportionate amount of ammonia compared to normal cells, because of these bacteria within our body that are disrupted and not functioning normally,” Bilchik added.
“Moreover, normal intestinal cells can detoxify this via the urea cycle enzymes, but colon cancer can’t do this very well as most of the enzymes in the urea cycle are decreased in cancer,” said Dr. Yatrik Shah, a professor of physiology, molecular and integrative physiology, and internal medicine at the University of Michigan Medical School and corresponding author of the study.
Stopping T cell interference
In this study, Shah and his team used a mouse model to find a high level of ammonia in colorectal cancer tumors that led to fewer T cells.
T cells are a type of white blood cell in the body’s immune system. They assist the body in fighting off infection and cancer.
“We think ammonia interferes with how T cells can generate antioxidant molecules like GSH,” Shah told Medical News Today.
When ammonia levels are heightened, researchers found colon tumors to be resistant to immunotherapy.
Still using a mouse model, scientists used FDA-approved drugs for hyperammonemia to reduce ammonia levels in colon cancer tumors, resulting in the tumors becoming more sensitive to immunotherapy treatment.
“Immunotherapies don’t work well in most colon cancers and we show that the resistance to this therapy is partially mediated by the effects of ammonia on T cells,” Shah explained. “Therefore, if we decrease tumor ammonia this enhances the efficacy of immunotherapies.”
Research next steps
When asked about the next steps for this research, Shah said there are several goals.
“First, figure out precisely what microbes are responsible for increasing ammonia in cancers,” he said. “Second, understand the metabolic pathways altered by ammonia in T cells. Third is to extend this finding to other types of cancers.”
“Lastly, we would like to perform trials in humans where we could use ornithine or glycerol phenylbutyrate to see if this would be beneficial in colon cancer patients,” he noted.
Bilchik added as this is an animal model study, the question is whether it will be applicable to humans or not.
“I think that this work is still in its infancy — there’s a lot that still needs to be done,” he said. “And then the next step would be given clinical trials, so a long way to go.”
Unique aspects to colorectal cancer
Medical News Today also spoke with Dr. Tanios Bekaii-Saab, a gastrointestinal medical oncologist at the Mayo Clinic Comprehensive Cancer Center in Arizona, about this study.
He stated in colorectal cancer, ammonia metabolism, and accumulation is highest versus other cancers.
“This relates to unique aspects in colorectal cancer, including two main sources of ammonia accumulation — cell autonomous metabolism and the presence of a unique microbial environment (microbiome),” Bekaii-Saab, who was not involved in the study, explained.
“The accumulation of ammonia in colorectal cancer preclinical models suggests a direct effect on deleting T cells that are thought to be key for the activity of immunotherapy,” he said when asked how this research might impact how doctors treat colorectal cancer tumors in the future. “Agents that deplete ammonia in settings such as hepatic encephalopathy appear to show interesting results in preclinical models. However, it is too premature to consider any of these agents or even this strategy in clinical practice.”
“More research is needed to validate the target and create more comprehensive strategies to consider integrating in clinical trials,” Bekaii-Saab added. “Some are already underway with understanding the role of microbiome and targeting strategies.”
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