Nerves talk to each other using chemicals called neurotransmitters. One of those “communication chemicals,” aptly named GABA (gamma amino butyric acid), shows up in unusually high amounts in some aggressive tumors, according to a School of Medicine study.
Researchers investigated metastatic neuroendocrine tumors, which include aggressive types of lung, thyroid and prostate cancers that spread to other parts of the body. Their study appeared in a recent issue of the Proceedings of the National Academy of Sciences.
“GABA appears to be an indicator of a bad prognosis for these cancers,” said Jeffrey I. Gordon, M.D., director of the University’s Center for Genome Sciences and the Dr. Robert J. Glaser Distinguished University Professor. “But there’s hope in our ability to identify substances, like GABA, that are associated with metastatic tumors.
“Usually these tumors are diagnosed only after they have spread to other parts of the body, but now we have the potential to recognize them before they metastasize.”
Elevated amounts of GABA were discovered in an analysis of aggressive neuroendocrine prostate tumors in genetically engineered mice. Along with GABA, two other substances were seen — one a related neurotransmitter and the other a plant-growth hormone with an unknown function in animals.
Furthermore, the researchers found that the tumors made GABA using a different set of biochemical reactions than normal. Key enzymes involved in the production of these compounds were switched on in poor-prognosis malignant metastatic tumors.
“The mouse model was an important beginning point for our investigation,” said the study’s lead author, Joseph E. Ippolito, a graduate research assistant in the University’s National Institutes of Health-supported Medical Scientist Training Program. “We took information about what genes were expressed in the mouse tumors, made computer-assisted predictions about what type of metabolism was going on in these abnormal cells compared to their normal noncancerous counterparts, and used new, powerful metabolite detectors to verify that these compounds were actually being made.
“We then took information gained from the mouse and asked whether the same human genes are expressed in poor prognosis as opposed to good prognosis human tumors. We found that the human genes that give rise to the key enzymes required to produce these metabolites were invariably switched on the poor prognosis but not the good prognosis tumor groups.”
Gordon added, “Most people understand the revolution in medicine to be a DNA-centered search for mutations in genes that cause disease. This study illustrates another layer of the revolution — understanding how certain diseases, in this case cancer, are linked to abnormalities in cellular metabolism — an area called ‘metabolomics.’
“We’ve described a unique tumor-associated pattern that we hope will provide new ways to diagnose these poor prognosis cancers earlier and to implement more effective treatments.”
The researchers believe that metastatic neuroendocrine tumor cells use GABA signaling processes to communicate with each other and with their environment.
“Through carefully planned clinical trials, we may be able to evaluate the therapeutic potential of already available drugs that affect GABA signaling to treat these aggressive types of cancers,” Ippolito said.
The association of GABA with aggressive tumors was uncovered by a novel combination of techniques that can now be employed for further identification of substances linked to tumors and other diseases.
The resulting information will significantly advance diagnosis and treatment options.
“We used a way to cross from basic sequence information in genomes to information about the substances likely to arise in tumors,” Ippolito said.
The researchers first analyzed the activity of genes in the mouse tumors using GeneChips, miniaturized arrays of gene sequences, to obtain information about how active each gene in tumors is.
They combined the mouse data with parallel data from 182 human tumors. Then, the gene-activity data was fed into sophisticated software that supplied the researchers with a prediction about which metabolic reactions were revved up in the tumors and which were slowed down.
The last piece of the puzzle was supplied by a highly sensitive instrument, called a mass spectrometer, that measured the products of cellular metabolism. The mass spectrometer measurements were cross-checked with the gene activity data and the predictions of metabolic reactions.
This set of techniques demonstrated the link between abnormal GABA production and aggressive tumors.
“We are able to examine not just genes, not just proteins, but the chemistry that underlies diseased tissues,” Gordon said. “Computational, experimental and instrumental tools are now available to tackle metabolomics and then translate lessons learned at the laboratory bench to the patient’s bedside, as called for by the University’s BioMed 21 initiative.”