UMD-led Study Sheds Light on How Incurable Form of Cancer Develops

Mesothelioma has been at the center of several high-profile multibillion-dollar lawsuits, but the rare and incurable form of cancer itself remains a medical mystery. Now, an interdisciplinary team of researchers from the University of Maryland may have identified an essential reason the disease develops and why it takes so long.

In a paper published in the journal Environmental Research, the team suggests that the key to understanding mesothelioma lies in how immune cells “sense” and interact with particles around them.

The disease develops on the lining of many internal organs—including the lungs and peritoneum—but its symptoms are often undetectable until about 40 years after initial exposure to asbestos, a common and naturally occurring mineral. About 4,000 cases of mesothelioma occur each year in the U.S., according to the Centers for Diseases Control and Prevention, including some in people who have no known exposure to asbestos, another source of perplexity to doctors and scientists.

According to the new study, the geometry of contaminant particles is more important than mineral composition.

“Asbestos kicks up an immune response when the immune system is exposed to the right shape and size of particle,” said study co-author and UMD Professor Emerita of Geology Ann Wylie.

The researchers believe the most dangerous kind of asbestos fibers, which are particularly thin and long, cause immune cells called macrophages to recruit other immune cells to asbestos exposure sites within tissue.

“This response prevents the immune cells from reaching other places where they’re needed, like precancerous lesions,” said study co-author Wolfgang Losert, a professor in the Department of Physics and the Institute for Physical Science and Technology at UMD. “This could cause the immune system to effectively ignore other serious conditions around that organ.”

In a previous study, some members of the research team found that mineral particles with diameters less than 250 nanometers and lengths greater than 5 micrometers were more difficult for the lungs to physically clear out than their shorter counterparts. For the new study, the researchers examined particles taken from mineral samples from various geological sites, and found that the human immune cells employed in the experiment used a mechanism called esotaxis to sense particles’ physical features and respond differently. Because longer particles are harder to dislodge, activated macrophages continue to call for more immune cells to the same site over a long period of time, dominating immune cell communication.

The researchers hypothesize that this “hijacking” of the immune cell migration system would lead to nearby regions of an infected organ to be neglected because all immune cells are delegated to a single site. As a result, other tissues would be deprived of the immune system’s healing abilities—a possible explanation of why immunocompromised patients can develop mesothelioma without known exposure to asbestos fibers.

“This response basically overwhelms the immune cell communication system and diverts the body’s own defenses away from where they’re needed,” explained study co-author John Fourkas, a professor in the UMD Department of Chemistry and Biochemistry and the Institute for Physical Science and Technology. “The physical characteristics of a mineral particle can change the behavior of immune cells in the long term, which could be why mesothelioma symptoms take a minimum of 30 to 40 years to manifest.”

The team believes that its theory also applies to other mineral particles that are similar in size to carcinogenic asbestos fibers. With rising concerns about the carcinogenic properties of airborne mineral particles like crystalline silica and carbon nanotubes, additional information about esotaxis and its effects on immune responses could help prevent other health problems.

“More research about the induction of cancer by minerals is still needed—it’s complicated and requires the expertise of geologists, chemists, physicists and bioscientists,” Wylie said. “But this project and others like it bring us a step closer to figuring out what mechanisms underlie not only mesothelioma but all types of cancer formations.”