New research has looked at human cancer cells implanted into mice, human tumor samples, and other assays in an attempt to better understand what drives the spread of certain aggressive cancers.
researcher studying samples in the laboratory
A ‘chemical messenger’ could be helping aggressive cancers grow and spread.

A team at Johns Hopkins Medicine in Baltimore, MD, has recently conducted a study, the results of which now feature in the journal Cell Reports.

These results indicate that many aggressive, or higher-grade, cancers contain higher levels of one specific neurotransmitter.

Higher-grade cancer tumors are characterized by faster growth and spread rates.

Neurotransmitters are chemical messengers that allow neurons to “communicate” among themselves and send messages to other cells.

In the new study, the researchers focused on N-acetyl-aspartyl-glutamate (NAAG), saying that this neurotransmitter may be a relevant new target when it comes to treating higher-grade cancer tumors.

Specifically, their experiments revealed that NAAG is more abundant in fast-developing cancer tumors than in other types of cancer. Also, the scientists found evidence to suggest that this neurotransmitter is a source of glutamate — an important cell nutrient — to certain cancer tumors, thus aiding their growth.

The tumors with high NAAG levels also expressed a certain ezyme: glutamate carboxypeptidase II (GCPII).

“Our study [suggests] that NAAG serves as an important reservoir to provide glutamate to cancer cells through GCPII, when glutamate production from other sources is limited,” explains senior study author Dr. Anne Le.

NAAG fuels some aggressive cancers

To begin with, the scientists used mass spectroscopy to analyze the composition of human Burkitt lymphoma cells. This technique allows us to assess the masses of different components within a study sample.

They found that MYC-driven Burkitt lymphoma, which expresses MYC gene alterations, had higher levels of NAAG that non-MYC-driven lymphoma. Also, this neurotransmitter was more abundant in human high-grade ovarian cancer tumors than in primary ovarian cancer tumors.

In short, fast-growing cancer contained significantly higher levels of NAAG than slower-growing cancer tumors.

Also, among human brain cancer tumor samples, higher-grade tumors had higher levels of NAAG than lower-grade tumors. These levels were “inversely and significantly correlated with patient survival time,” the study authors write.

This means that more aggressive tumors contained higher levels of this neurotransmitter, and that the people from whom the scientists collected those tumor samples were less likely to have survived.

Targeting two culprits at once

Their next step involved investigating mouse models in which they had implanted human Burkitt’s lymphoma tumors. Looking at the rodent model, they found that as tumors grew, their NAAG content also rose. Conversely, if any tumors shrank, their NAAG levels also declined.

Then, working with mouse models in which they had implanted human ovarian cancer tumors, the scientists tried to fight GCPII activity by using an inhibitor called 2-PMPA.

This allowed them to both shrink the tumors and reduce concentrations of glutmate in the cancer cells.

Finally, when looking at mice with human-derived pancreatic cancer tumors, the scientists saw that by attacking glutaminase — which is an enzyme that converts glutamine into glutamate — as well as GCPII, they were able to shrink cancer tumors even further.

This, the researchers argue, is likely because they stopped the production of the cell nutrient from two sources: NAAG and glutamine.

“Together,” notes Dr. Le, “these findings strongly link plasma concentrations of NAAG with tumor growth rates, and suggest that measurements of NAAG in peripheral blood should be further explored for timely monitoring of tumor growth during cancer treatment.”

“These results don’t make NAAG a potential diagnostic marker, but a prognostic marker,” adds Dr. Le, “a potentially valuable way for noninvasive assessments of tumor progression.”

NAAG is ‘a hidden reservoir’

Dr. Le also cites previous research that had already suggested that glutamine metabolism may help drive cancer growth.

“Seven years ago, we found that glutamine was a big deal in cancer metabolism, and inhibiting the conversion of glutamine to glutamate was the right target to curb cancer growth,” says Dr. Le.

It turns out, that’s correct. But it’s not enough, because cancer cells have another way to make glutamate through this hidden reservoir. Targeting both pathways could improve cancer treatments.”

Dr. Anne Le

However, she specifies that the recent findings are only relevant to cancer tumors that express GCPII.

She does not discount that NAAG may promote tumor growth in other types of cancer, too, though this may occur through different channels. The team would have to conduct further studies to assess the veracity of this hypothesis, cautions Dr. Le.