UGA researchers develop non-invasive early diagnostic test for gastric cancer

Early detection of cancer may eventually become as easy as taking a home pregnancy test, according to new University of Georgia research.

Two studies recently published in the journal PloS ONE identified for the first time that certain proteins excreted in urine can indicate the presence of gastric cancer.

The researchers initially studied stomach cancer because it is the number two cancer killer in the world.
They hope that with further study, the detection of abnormally abundant proteins in urine will lead to diagnosis of many types of cancer and other diseases, said Ying Xu, lead author of the study and Regents-Georgia Research Allianceeminent scholar of bioinformatics and computational biologyin the UGA Franklin College of Arts and Sciences.

“In theory, the methodology that we developed should be applicable to other cancers,” said Xu, who also is a professor of biochemistry and molecular biology and director of the UGA Institute of Bioinformatics.

Xu and his colleagues, Celine Hong, Juan Cui and David Puett of the Institute of Bioinformatics, identified a protein called endothelial lipase that differed significantly in its abundance in urine samples of stomach cancer patients versus healthy people. Xu said the computational capability presented in the study for predicting which of the abnormally abundant proteins in diseased tissues can be excreted into urine is a key breakthrough in cancer detection. Using samples from already known excretory and non-excretory proteins, the study found that the classification system was more than 80 percent accurate.

Of the 21 urine samples of healthy people, only two did not have the protein. In the 21 urine samples of stomach cancer patients, only one sample was considered to have a relatively high level of the protein; levels in the rest were low or absent. “We are suggesting from this relatively small urine sample set that healthy people should have this protein in their urine,” Xu said.

The researchers are currently working on a larger urine sample set of 200 gastric cancer patients and 200 healthy people. “If the EL protein still has the 10 to 15 percent miscalculation rate as with the 21 versus 21 samples, I think we have found a good diagnostic marker for stomach cancer and potentially other cancers,” said Xu.

Now that the researchers have identified a protein marker, Xu says they should be able to develop a method where urine can change the color of a piece of paper to indicate the presence or absence of the protein, similar to the way a home pregnancy test works. The researchers hope to find multiple protein markers for each cancer to increase the accuracy of the test.

Although the test is not yet 100 percent accurate, it can lead at-risk patients to seek a more comprehensive exam, said Xu. Current procedures such as endoscopy are invasive, uncomfortable and may be avoided by many people. “A person could go get a urine test, and if the marker protein is present, then they are generally stomach-cancer free,” said Xu. “If the protein is not present, we might suggest that they get their stomach checked.”

The researchers began by studying a set of 1,500 proteins known to be excreted in urine and identified a list of features that distinguish them from proteins that are not excreted into urine. Identifying these distinguishing features allowed them to develop a classification system that could predict which proteins in cancerous tissues are excreted into urine.

Xu and his colleagues then used microarrays—chips that are about the size of a stamp that contain nearly twenty thousand human genes—to identify which proteins varied in abundance in the cancerous versus non-cancerous tissues. Messenger RNA (mRNA) molecules extracted from the sample tissues are converted to complementary DNAs (cDNAs) and hybridize with their complement genes on the microarray and light up as spots when the corresponding mRNAs are abundant. The researchers then identified proteins corresponding to those genes that appeared at significantly different levels in the cancer and non-cancer samples. From there, the researchers were able to determine which of the abnormally abundant proteins were secreted into the blood and then excreted in urine using the classification method they developed.

The UGA researchers work in conjunction with a team of researchers led by Fan Li of Jilin University in China, where Xu spends two months a year working with medical doctors and researchers on sample collection and carrying out microarray experiments. This long-term collaboration has led to the establishment of the Jilin University/University of Georgia Joint Research Center for Systems Biology. The researchers are currently collecting tissues from patients with different types of cancer to identify more protein markers that can be detected in urine.

The study was supported by the UGA President’s Venture Fund, the Office of Vice President for Research, the Georgia Cancer Coalition, the Georgia Research Alliance, Jilin University and the National Institutes of Health.

To learn more about the UGA Institute of Bioinformatics, see http://www.bioinformatics.uga.edu/. To learn more about the Franklin College of Arts and Sciences department of biochemistry and molecular biology, see http://www.bmb.uga.edu/.

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Natural system for eliminating salt may point to new antihypertensives

A study of the body system that deals with Americans’ love affair with salt may yield more insight into why so many end up hypertensive and how to better treat them.

A team of scientists from the Medical College of Georgia, the University of Utah and the University of Texas at San Antonio is looking at how the kidneys know you’ve eaten too much salt and what they do to eliminate it. The work is funded by a $11.2 million National Institutes of Health Program Project grant.

Their focus, endothelin, ironically has a bad rep as a “death peptide” because of its shared ancestry with the Israeli burrowing asp that can shut down coronary arteries with one bite.

But the powerful protein produced by the kidney takes direction – good or bad – from its receptors, according to Dr. David Pollock, renal physiologist at MCG’s Vascular Biology Center and director of the program project.

“It’s like politics: all things are local,” said Pollock.  In this case the upright guy tends to be the B receptor, which aids sodium excretion while its roguish sibling A receptor – the same one that shuts down the coronary arteries of asp victims – blocks it. When all goes well, the balancing act regulates the sodium level with the kidneys producing more endothelin and B receptors to eliminate the excess.

However in hypertension models, the B receptor doesn’t work so well, although exactly why is still unclear. “It’s this balance between A’s and B’s that is critical,” Pollock said. “If your balance becomes unbalanced you will have salt-sensitive hypertension.”  That’s why he is looking at the pathways that become activated on a high-salt diet and just what the A receptor is up to.

He and his colleagues are studying rats deficient in B receptors; they are a slightly hypertensive on a regular diet and very hypertensive on a high-salt diet.  More circuitously, the researchers also infused angiotensin, a powerful blood vessel constrictor, into rats causing similar dysfunction of the B receptors.

“We also think without the B receptor function, your A’s go a little bit crazy,” Pollock said. Not only do the A’s constrict, they promote inflammation, which can further damage blood vessels. In fact, a high-salt diet can cause even B receptors to behave badly, said Dr. Jennifer Pollock, MCG biochemist and a project leader.

Across the country, Dr. Donald Kohan, nephrologist and physiologist at the University of Utah, wants to figure out what prompts the kidneys to make more endothelin in the face of a high-salt diet. He is studying kidney cells to examine how endothelin production changes and ideally learn why. The goal, again, is drug therapies to inspire this natural phenomenon.

The results when A receptors go unchecked include stiff, tortuous blood vessels; a thick boggy pumping chamber in the heart; and other major organ damage that includes the kidney.

“The consequences are measurable targets,” said Dr. Edward Inscho, MCG physiologist and a project leader, noting that treatments are available but “preventing it from occurring is something we are not very good at yet.”

To help put the pieces together, Inscho is focusing on how blood vessels that feed directly into kidney filters react to a high-salt diet. Blood, containing salt, continuously flows through the kidneys. The researchers have seen that excess salt increases B receptor expression, which should help the kidneys filter more sodium then get rid of it.

“If you filter more, you have more salt available for excretion,” Inscho said. He wants to know what’s happening with A and B receptors inside the tiny vasculature of the kidneys. He’s using B-deficient rats and drugs that block either receptor to get a better idea about both. The idea is to figure out not just how they normally work but how the system becomes dysfunctional in hypertension.  “I think we are beginning to understand how the B receptor may factor into some other regulatory systems the kidney may use to control filtration,” he said.

Noted Jennifer Pollock, “Your kidneys in theory should be able to lower your blood pressure but because people do remain hypertensive, that means there must a problem with your kidneys as well.” She suspects that endothelin activates production of nitric oxide when it hits the B receptor. Nitric oxide, which dilates blood vessels, prompts the sodium channels in kidney tubules to fold inward.

“The salt can’t get in and so it gets excreted,” Jennifer Pollock said. “We are connecting the dots now.” If they are correct, they have found a new mechanism for controlling salt excretion that is a natural drug target. Since it’s difficult to enhance nitric oxide, it likely will be necessary to find another cue to prompt sodium channels to fold up their tents. She developed a mouse lacking nitric oxide synthase, which prompts nitric oxide production, to help pursue the theory.

Co-investigator Dr. James Stockand in Texas is investigating mechanisms for how endothelin affects transport of sodium in and out of the cell, focusing on proteins known as ion channels. Dr. Jennifer Sullivan, pharmacologist/physiologist at MCG’s Vascular Biology Center, is providing support and expertise with the numerous animal models needed for the grant.

“The future of pharmaceutical therapies is going to be the right balance of different drugs,” said David Pollock.  “Most people with high blood pressure are also taking cholesterol medicine and possibly other drugs. So the future has to be what is the right formula for you and your situation.”

The scientists hope their studies will point the way to these new, targeted options.

By Toni Baker
Medical College of GA

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