Scientists have discovered a mechanism by which the most aggressive brain tumors in adults can stimulate surrounding nerve cells and accelerate their own growth. The study showed that virtually all high-grade gliomas accumulate large amounts of the metabolite guanidinoacetate (GAA). It activates neurons near the tumor, which in turn stimulate the division of cancer cells. The findings were published in the journal Cell.
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Researchers from the Research Institute at Children’s Medical Center at UT Southwestern Medical Center found that the concentration of GAA in these tumors can be approximately 100 times higher than normal.
This occurs because of excessive activity of the enzyme that produces GAA. When tumor cells become overloaded with the substance, another enzyme, GAMT, is no longer able to convert all of the excess GAA into creatine. As a result, GAA is released from the cancer cells into the surrounding tumor tissue.
There, it binds to receptors on nearby neurons and activates them. The activated nerve cells begin transmitting chemical and electrical signals that stimulate the proliferation of glioma cells.
The researchers confirmed the link between GAA and neuronal activity in a series of experiments. When they blocked the enzyme responsible for producing GAA in tumor cells, the level of the metabolite decreased, neuronal activity was reduced, and tumor growth slowed. At the same time, artificially activating neurons enabled them to stimulate tumor growth even in the absence of excess GAA.
Another experiment showed that the effect depends specifically on interactions between tumor cells and neurons. When cancer cells were grown without nearby nerve cells, lowering GAA levels no longer slowed their proliferation.
The researchers noted similarities between this mechanism and a rare inherited metabolic disorder — GAMT deficiency. In this condition, GAA also accumulates, and symptoms can include seizures and other neurological problems.
The next step will be to investigate a potential treatment. The researchers plan to test a special dietary therapy that is already used for GAMT deficiency in patients with high-grade gliomas. Before surgery, patients will modify their diet, after which researchers will be able to determine from samples of the removed tumors whether GAA levels were successfully reduced.
If dietary modification does indeed lower metabolite levels in tumors, subsequent studies will be able to determine whether this approach improves treatment effectiveness and patient survival.
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