Stroke Remodels Tumor Microenvironment to Promote Glioma Growth

The results of a study by researchers at Texas Children’s Duncan Neurological Research Institute (Duncan NRI), at Baylor College of Medicine and collaborating institutions have shown that stroke promotes glioma growth, and point to cellular and molecular mediators involved in the process, linking brain injury to malignant brain tumors.

Working with mouse and human models, the team discovered that stroke induces tumor microenvironment (TME) remodeling, alongside the emergence of a distinct population of tumor-associated astrocytes (TAAs) exhibiting reduced Ca²⁺ activity, and enrichment of tumor-associated microglia and macrophages (TAMs). Restoring TAA Ca²⁺  signaling or depleting TAMs, suppressed stroke-induced glioma progression, pointing to the importance of both cell type types in injury response.

Research lead Hyun Kyoung Lee, PhD, principal investigator at the Duncan NRI, and an associate professor of pediatrics – neurology and member of the Dan L Duncan Comprehensive Cancer Center at Baylor, and colleagues reported on their findings in Nature Cancer, in a paper titled “Stroke drives glioma progression through the emergence of tumor-associated astrocytes with reduced Ca²⁺ activity.” In their paper the investigators concluded, “Collectively, our findings establish stroke-induced remodeling of astrocytic Ca²⁺ signaling and TAMs as drivers of glioma progression and link brain injury to malignant disease.”

Glioblastoma (GBM) is the most prevalent and aggressive malignant brain tumor in adults,  and has what the researchers describe as “… a notably dismal 5-year survival rate.”  Research has catalogued a number of genetic mutations associated with GBM, the team pointed out, but the risk factors predisposing individuals to glioma are not well understood. “Recent clinical cohort studies and case reports have identified a correlation between glioma and brain injuries, where ischemic stroke shows significant co-occurrence with brain tumors, including glioma,” they further noted.

Lee added, “Epidemiological and clinical studies suggest that patients with a history of stroke or traumatic brain injury are at increased risk of developing brain tumors.  The risk can be about three-fold to seven-fold, depending on the age and sex of the patient.” However, Lee continued, “Despite these clinical observations, the mechanism that connects brain injury and cancer remains unclear.”

For their newly reported study the researchers, including Qi Ye, PhD, and graduate student Christine Madamba, at the Lee lab, worked with human and mouse models to investigate whether stroke promotes glioma growth and the factors mediating the connection. The team discovered the emergence of a distinct population of brain cells—tumor-associated astrocytes—with distinct physiological and molecular characteristics, including diminished calcium activity. TAAs were accompanied by the accumulation of two other cell types, remodeled tumor-associated microglia and immune cells called macrophages (TAMs). “Mechanistically, we identified SLC4A4 as a key regulator of Ca²⁺  activity in TAAs and CCL2-mediated TAM recruitment,” they reported in their study.

The researchers also showed that restoring TAA calcium signaling or removing TAMs suppressed stroke-induced glioma progression, “… identifying both populations as critical mediators of the stroke response.” The findings suggest that these injury-induced, tumor-promoting pathways are potential therapeutic targets and support continuing research into strategies that could reduce the risk of glioma growth in patients with a history of brain injury.

“We show that stroke promoted tumor infiltration into injured brain regions in human and mouse glioma models, and reduced overall survival,” Lee said. “Looking closer into the cellular and molecular makeup of the tumors, we found that stroke triggers remodeling of the tumor microenvironment.”

The authors stated “In summary, our study reveals that ischemic stroke remodels the TME to promote glioma progression, highlighting injury-induced tumor-promoting pathways as potential therapeutic targets for persons with a history of brain injury … More broadly, our work establishes a framework for investigating TAA-mediated immune regulation, TME remodeling, and the mechanisms linking brain injury to glioma progression and tumorigenesis.”

Lee added, “Our study supports that brain injury can be a risk factor for brain cancer. In addition, our findings contribute to growing evidence pointing at a role of astrocytes in brain tumor growth. Neuron-tumor interactions have been shown to contribute to cancer growth. We show that other brain cells, astrocytes, also seem to communicate with brain cancer cells and influence their behavior. They should be considered when studying cancer mechanisms and therapies.”

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