Exercise May Stop Cancer from Spreading to the Brain

NCI CAM Annual Report-FY10

Michal Toborek, M.D., Ph.D., has devoted much of his research to the blood-brain barrier, which appears to have an important role in some metastatic cancers. Metastases are the cause of most cancer deaths, said Dr. Toborek, “and the number of people who develop cancer in the brain (primary or metastatic) each year is enormous, probably around 200,000 in the United States alone.” Only about 1 in 9 of these people have primary brain tumors, he added, while the rest develop metastatic brain cancer that originated in other organs.

For years, researchers have been trying to learn about and prevent the process of metastasis. Because metastatic cancer cells travel through the bloodstream, if they are turned away by the blood-brain barrier, you will prevent cancer metastasis to the brain, explained Dr. Toborek, who is a professor in the Department of Neurosurgery at the University of Kentucky. The capillaries feed the brain with nutrients from the bloodstream such as glucose and amino acids, he said. There are certain protein structures known as transporter systems that recognize and send these vital nutrients across the blood-brain barrier, he continued, but other foreign substances and other cells that arrive via the capillaries – from cancer and other diseases – are recognized as intruders and cannot get into the brain.

What stops them are the endothelial cells that make up the barrier and stick together like bricks. The metaphor extends to the “mortar” that holds them together, which are various types of adhesion molecules, Dr. Toborek said. What is new about his research is the recognition that exercise helps to keep these joints tightly bound together; they are referred to as “tight junctions.” It has been found that these junctions can be compromised by oxidative stress, which often occurs when any of a number of foreign substances – tumor cells or cells from the body’s hormone and immune systems – arrive at the blood-brain barrier, he commented.

With NCI support,* Dr. Toborek’s lab is studying how certain proteins that fortify these tight junctions against oxidative stress are enhanced by exercise. They have developed a mouse model to explore this phenomenon. The mice are trained as runners on a wheel in their cage, and are genetically engineered to be especially vulnerable to brain metastases. After some animals are rigorously trained for 5 weeks, and others remain sedentary, the researchers inject lung cancer cells into their carotid arteries, which is the access route that metastatic cancer cells would naturally travel in the circulatory system if they were headed for the brain. The results showed that the fit animals had dramatically fewer cases of brain metastases.

If the promising findings in the mouse studies can be confirmed in clinical trials of human patients, the public health impact of this line of research could be significant, Dr. Toborek commented. “This work follows a lot of compelling evidence that show that exercise reduces cancer risk by up to 50 percent in breast and colon cancer,” he noted. The challenge is that currently 3 in 5 Americans don’t exercise regularly and 1 in 4 Americans are limited to a sedentary lifestyle, he added.