Central nervous system (CNS) lymphoma is a rare non-Hodgkin lymphoma in which malignant B cells from lymph tissue form in the brain and/or spinal cord or spread from other parts of the body to the brain and/or spinal cord.

Abnormal leaks in the blood-brain barrier have previously been linked to the severity of CNS lymphoma. However, the molecular details remain unclear. Now, researchers at Gladstone Institutes have shown in mice that CNS B-cell lymphoma cells cluster at sites where there is a leak in the blood-brain barrier. They also found that a blood protein called fibrinogen, which normally participates in blood clotting, promotes this clustering.

Their study, “Blood Coagulation Factor Fibrinogen in Tumor Pathogenesis of Central Nervous System B-Cell Lymphoma,” was published in the American Journal of Pathology.

“CNS lymphoma is an extranodal non-Hodgkin B-cell lymphoma characterized by malignant lymph tissue arising in the brain or spinal cord, associated with inflammation and blood-brain barrier (BBB) disruption,” the researchers wrote. “Although BBB disruption is known to occur in patients with CNS lymphoma, a direct link between these two has not been shown.”

Gladstone scientist Jae Kyu Ryu, PhD, (right) and his colleagues discover new links between lymphoma growth and leaks in the blood-brain barrier. [Gladstone Institutes]
“Our findings link, for the first time, fibrinogen with CNS B-cell lymphoma, shedding new light on mechanisms of lymphoma growth in the brain that could be further explored as a treatment target,” said senior author Jae Kyu Ryu, PhD, staff research scientist at Gladstone Institutes.

The researchers observed abundant buildup of fibrinogen around CNS lymphoma tumors in tissues from both human patients and a mouse model of the disease. Using bioinformatics tools, the researchers identified fibrinogen and other blood-clotting proteins in the brain fluid of B-cell lymphoma patients connected with tumor-associated alterations in biochemical pathways.

“Using live imaging of the mouse brain, we found that the cells accumulated at sites of leakage in the blood-brain barrier and tended not to stray from the leaks,” said Justin Chan, MD, first author of the study and undergraduate research intern at Gladstone, who is now a resident physician at the School of Medicine at the University of California, Irvine.

The researchers demonstrated that CNS lymphoma cells can stick to fibrinogen, but not to every other protein found in mouse blood.

“That was kind of an ah-ha moment that pinpointed fibrinogen as a key protein that allows CNS B-cell lymphoma cells to adhere to the leakage sites in the brain,” Ryu explained.

“Fibrinogen is a common thread among multiple neurological and peripheral inflammatory diseases,” said study co-author Katerina Akassoglou, PhD, who is the director of the Gladstone-UCSF Center of Neurovascular Brain Immunology, a senior investigator at Gladstone, and a professor of neurology at UCSF. “The new findings may reveal unanticipated mechanisms at the intersection of the vascular, brain, and immune interface in brain B-cell lymphoma, as well as novel targets for therapies and biomarkers.”

The findings suggest that fibrinogen may serve as a new therapeutic target to treat CNS B-cell lymphoma. The researchers noted that although existing drugs that disrupt fibrinogen’s activity may be an attractive strategy, these drugs could excessively disturb the protein’s beneficial blood-clotting role and lead to dangerous side effects, such as increased risk of tumor metastasis.

The researchers have developed an immunotherapy that blocks the specific role played by fibrinogen in neurological diseases, without disrupting the blood-clotting process.

“Our new findings provide an exciting foundation for future studies on developing strategies to precisely block the lymphoma-promoting activity of fibrinogen,” added Ryu. “This could help us identify very specific aspects of fibrinogen’s activity that could be targeted safely and effectively.”

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