Early Detection of Mesothelioma Lies in HMGB1 Isoforms
An international research team is exploring how variants of an important blood protein could be the key to prevention and early detection of malignant mesothelioma.
Dr. Haining Yang at the University of Hawaii Cancer Center is leading the research and recently presented potential strategies at the 6th International Symposium on Malignant Pleural Mesothelioma.
Previously, Yang and her team showed how the High-Mobility Group Box 1 (HMGB1) protein sparks the proliferation and survival of cancerous mesothelioma cells.
Yang and colleagues recently discovered that isoforms or “protein variants” of HMGB1 could be a key to early detection of the asbestos-related cancer.
Yang’s team discovered mesothelioma cells secrete HMGB1 actively and make hyper-acetylated HMGB1 isoform for the secretion. Instead, normal mesothelial cells exposed to asbestos die, and passively release non-acetylated HMGB1.
“Mesothelioma cancer patients have the hyper-acetylated isoform of HMGB1 in their blood,” Yang told Asbestos.com. “People exposed to asbestos who do not have cancer yet, have instead, high amounts of HMGB1, but the isoform is non-acetylated.”
Importance of HMGB1 Protein in Mesothelioma
Typically, asbestos fibers cause cell death in human mesothelial cells. These cells comprise the mesothelium membranes that line the pleura, pericardium and peritoneum.
Previous research from Yang’s team shows crocidolite, the most carcinogenic type of asbestos, caused a high percentage of cell death in cell cultures.
“We know asbestos causes cancer, especially mesothelioma,” Yang said. “The question was how can these fibers cause cancer if they cause cell death?”
Through a series of studies, Yang’s team determined the answer lies within the HMGB1 proteins. Mesothelial cells exposed to asbestos die through a process called necrotic cell death, which releases HMGB1. Extracellular HMGB1 initiates the inflammatory reaction that, over the course of many years, may promote the growth of malignant mesothelioma.
The immune response triggered by HMGB1 helps asbestos-damaged mesothelial cells survive. However, over the course of many years, those damages cause the cells to become malignant.
Malignant mesothelioma cells contain high levels of HMGB1 in the nucleus and cytoplasm. They also actively secrete HMGB1 to the extracellular space. While detecting these high HMGB1 levels could be a key to early detection of mesothelioma, identifying the specific isoform of the protein in people with a history of asbestos exposure could prove even more beneficial.
“By detecting the levels of HMGB1 and its isoform in the blood, we can recognize the population that is at high risk,” Yang said. “We can monitor them and try to detect mesothelioma at an early stage when this cancer is more susceptible to therapy. That is what we hope to do in the future.”
Collaboration and Larger Cohorts Are Essential
Monitoring and checking those high-risk groups and observing an isoform change from non-acetylated to hyper-acetylated would suggest malignant tumor growth.
“By doing that, we hope we can catch the development of the cancer in the earliest stages,” Yang said.
Because it is rare and has symptoms that mirror other cancers or less serious illnesses, mesothelioma is often diagnosed in late stages when potentially curative surgery is no longer an option. Yang also noted there is little difference between early- and late-stage mesothelioma patients on HMGB1 levels, which makes it a valuable tool for early detection.
To understand the isoforms better and how they play a role in the development of mesothelioma, Yang said larger studies and more samples are needed. Because mesothelioma is such a rare disease, collaboration is necessary for future progress.
“In the United States each year, about 3,000 new cases of mesothelioma are diagnosed. We try to encourage collaboration and share resources to accelerate progress and find better ways to prevent and treat mesothelioma.” she said.
“The mesothelioma field is small,” Yang said. “It’s a rare cancer, so we need to work collaboratively with experts in different fields of medicine and science, and we also need to work collaboratively with other hospitals and universities. We need to pool together resources and expertise to rapidly develop new and more effective therapies.”
Detecting total HMGB1 can be done fairly easily with a commercial kit in any lab or clinic, but determining the different isoforms of the protein is much more difficult.
“So far the only technique that has been developed is using the mass spectrometry assay,” Yang said.
The University of Hawaii Cancer Center and other labs around the world are exploring easier ways to detect the isoforms.
“So far, unfortunately, no one has succeeded yet,” Yang said.
HMGB1 and Other Cancers
HMGB1 is at the highest levels in mesothelioma patients, but the protein might be a useful biomarker also for other cancers such as pancreatic cancer.
Yang said that based on preliminary data, HMGB1 levels are higher in mesothelioma patients than in other cancer patients, probably because of the biopersistence (length of time it remains in the lung) of asbestos fibers.
“[Asbestos] fibers are very persistent, so they continuously cause cell death and inflammation, and those cells release HMGB1 to the blood,” Yang said.
Currently, scientists are not sure if the different isoforms of HMGB1 are the “cause or outcome” of the development of mesothelioma.
“Although we’re focusing on it as a biomarker at this moment, the [Department of Defense] Translational Team Science Award that my colleagues and I won recently will support our studies on the mechanisms,” Yang said. “We hope to find out how HMGB1 and its isoforms promote the development of mesothelioma.”
Previous studies show targeting and inhibiting HMGB1 reduces malignant mesothelioma cells’ proliferation, mobility and anchorage independent growth.
In 2015, Yang’s team discovered that aspirin can inhibit the growth of mesothelioma tumor cells by blocking the inflammatory effects of HMGB1.
“By using aspirin to inhibit tumor growth in mesothelioma, we found other activities of aspirin that can be adapted to other cancers and diseases as well,” Yang said. “Although it is a rare disease, mesothelioma is a very good model to help us understand many things.”
In parallel research conducted with Carbone, Yang’s team discovered BAP1 gene mutations predispose people to mesothelioma and other cancers.
They are now monitoring those high-risk families for HMGB1 levels they hope will help them detect mesothelioma at an early stage.