Exposure to ammonia found to amplify breast cancer cell proliferation.
Cancer cells are constantly adapting to bypass natural and drug interventions that aim to kill tumors. These factors result in some cancer cells proliferating even after different types of treatments.
Breast cancer cells have been observed to use a byproduct of cell metabolism to increase tumor growth, according to a study published by Science. The authors found that the cells used ammonia as a source of nitrogen to facilitate proliferation.
The authors also found that ammonia can amplify cancer growth in cultured breast cancer cells and that inhibiting ammonia metabolism could reduce tumor size.
These findings may identify a previously unknown biological role of ammonia in cancer and could lead to the development of novel treatments, according to the study.
“Classically, ammonia was thought to be metabolic waste that must be cleared due to its high toxicity,” said senior study author Marcia Haigis, PhD. “We found that not only was ammonia not toxic for breast cancer cells, it could be used to feed tumors by serving as a source for the building blocks that tumors need to grow.”
Cancer cells consume nutrients to sustain growth, which produces excess waste that is transported to the liver. Once in the liver, byproducts are then converted into less toxic substances and excreted.
Since tumors have limited blood vessels, ammonia aggregates in concentrations high enough to kill healthy cells, according to the authors.
The investigators labeled nitrogen on glutamine to determine how tumors survive an environment high in ammonia. When glutamine is broken down, ammonia-containing nitrogen is the resulting byproduct.
The researchers then examined more than 200 cellular metabolites in cell models and human tumors transplanted into mice models.
They found that cancer cells integrated ammonia into several functions, including glutamate amino acid and its derivatives, according to the study. The authors noted that nitrogen was incorporated into 20% of the cellular glutamate pool.
In cell models, the prevalence of ammonia increased growth, with cells doubling up to 7 hours faster than cells not exposed to the byproduct. In 3D cultures, ammonia exposure increased cells and clusters up to 50%, according to the study.
The presence of ammonia was also observed to increase tumor growth in mouse models. When glutamate dehydrogenase was blocked, tumor growth was reduced, suggesting a potential treatment strategy.
“We found that repressing ammonia metabolism stunts tumor growth in mice,” said first author Jessica Spinelli. “Therefore, inhibition of ammonia assimilation or ammonia production may be rational strategies for therapy design.”