BOZEMAN – A Montana State University scientist recently published research that may explain how some cancerous tumors persist and continue to grow even after undergoing treatments that kill the cancerous cells.
The new findings were published in June in the journal Cell Reports and come from furthering research published two years ago in Nature Communications that described a “backup system” in mammals that acts as a generator, kicking in to sustain liver function when the liver’s two main systems fail.
“One of the surprising and most important take-home messages from the Cell Reports paper is that we now have an understanding that the reason we have the system we previously discovered is because it’s so critical for us to have multiple levels of back up,” said Ed Schmidt, professor of genetics and development in the Department of Microbiology and Immunology in MSU’s College of Agriculture and College of Letters and Science.
Schmidt and his collaborators at the Karolinska Institute in Sweden were surprised by their findings of the third system described in the 2015 paper because research conducted 50 years earlier suggested there were only two enzyme systems -- thioredoxin reductase and glutathione reductase -- that protect DNA and cells from oxidative damage through chemical reactions called “disulfide reduction reactions.”
Oxidative damage occurs in organisms that use oxygen and is caused by the body’s inability to counteract or neutralize the effects of free radicals. It is thought to cause aging, cancer and damage to DNA, Schmidt said.
“We need this reduction reaction to replicate DNA so a cell can divide, or to repair damage; we need it to make other building blocks besides DNA; and we need it to act as an antioxidant system and protect against oxidative damage,” Schmidt said.
The 50-year-old study showed that when both thioredoxin and glutathione were removed from simple organisms such as bacteria or yeast, the organisms would die. Because of those results, Schmidt said, the thought was that if basic cells like bacteria couldn’t live with both enzymes removed, then nothing could.
It was when Schmidt’s research team removed the two enzymes from the livers of mice and found that the mice survived that they discovered the "backup" system, which is fueled by a sulfur-containing amino acid called methionine.
“This pathway isn’t used much and it doesn’t exist in primitive species, but it is robust and able to do the job,” Schmidt said, adding that the system kept the liver functioning for the normal lifespan of the mice.
For the new study, the researchers increased the amount of oxidative stress on the mouse model livers that only had the backup pathway to rely on and found that the liver cells could not protect themselves from damage.
“Now, we thought, the mice would be really susceptible and would die, but what we found is they didn’t die,” he said. “Again, we asked why and looked at the livers and we saw tons of damage and cells dying, but the liver was surviving and, therefore, the mouse was surviving.”
The researchers learned that the liver cells were dividing 300 times faster than normal to replace the damaged and dying cells caused by the added oxidative stress. But, Schmidt said, there was another puzzle to solve. For cell division to increase by 300 times, the cells have to make just as many DNA building blocks, which requires the main systems that the researchers had removed.
Further research showed that while the thioredoxin reductase and glutathione reductase systems require a lot of energy to protect itself against oxidative damage, it only takes a small amount of energy to make the DNA precursors, or building blocks, that cells need to replicate and divide.
“This was very interesting and unexpected, and when we started thinking about it, this isn’t the only place that this happens,” Schmidt said. “This is exactly what you see in cancerous tumors, where there is tons of oxidative stress and damage occurring to cells and the cancer cells are dying like mad, possibly because of chemotherapeutic drugs or radiation therapy, but the tumor keeps growing back and can eventually kill a person.”
Schmidt said it is likely mammals, as higher organisms, developed the third pathway, or backup system, to enable them to survive some toxic exposure and go on to reproduce and keep their species alive. But, this same system has also given cancers a way to protect themselves from the mammalian immune system and environment.
Schmidt and his colleagues are now looking to better understand this third pathway and see if there is a way to make it more robust to better protect against toxicity in the liver, such as in the many cases of acute liver failure caused each year by Tylenol pain reliever.
“Tylenol goes into all the cells of the body, but in liver cells it’s activated by the liver’s defense systems that turn it into something toxic,” Schmidt said. “This activated Tylenol blocks both pathways –the thioredoxin reductase and glutathione reductase pathways – and now the cells are in trouble and many die and this leads to acute liver failure.
“If there were a way to make the backup system stronger, we could be more resistant to a high dose of Tylenol.”
They also want to use their new knowledge to better understand cancer in the hopes of coming up with additional treatments.
“Cancer therapy has come a long way and it’s remarkable how many cancers are treatable now, but there are still some nasty ones, like liver cancer, that aren’t,” Schmidt said. “It’s possible that a better understanding of these mechanisms might lead to new ideas that give us an alternative way to combat these challenging cancers.”
Professor Mark Jutila, who heads MSU's Department of Microbiology and Immunology, lauded Schmidt's expertise and dedication to his research.
"Dr. Schmidt is an internationally recognized expert in the use of novel genetic models to unravel complex biological processes in the animal," Jutila said. "This outstanding paper is a culmination of years of earlier preparatory and collaborative studies, which benefited from a sabbatical in which Dr. Schmidt spent a year working with his colleagues in Sweden.”
Contact: Ed Schmidt, associate professor in MSU's Department of Microbiology and Immunology, firstname.lastname@example.org or 406-994-6375