Melanoma, when it metastasizes, has a high likelihood of spreading to vital organs such as the brain. Although treatments have gotten better for melanoma patients overall, because of the increase in melanoma rates and treatments to prolong the lifespans of melanoma patients, it also means that now there are more diagnoses of melanoma-involved brain metastases. Obviously, this prospect is a scary one for patients and their families as the survival rates are terrifyingly low once melanoma invades this organ. Recent research from a team at Tel Aviv University may crack open the door towards more effective ways to halt melanoma’s advances towards the brain.
First, a bit of brain biology. Within the brain are cells called astrocytes. These astrocyte cells are kind of like mall cops for the brain. Their role is to protect the brain; and while they may not have the high-powered weapons of the immune system, they can trigger an alert to bring in the big guns by activating inflammatory pathways for the immune cells. The alert that the astrocyte cells produce is an inflammatory factor called CXCL10.
Although the team looked at mice who developed spontaneous brain metastases, they also looked at human brain tissue of people with brain melanoma and found that both mice and humans (and likely other mammals) produce CXCL10. But the really interesting discovery was that melanoma basically hijacks the pathways the astrocyte cells create with CXCL10, using those pathways as an express highway into the brain. Melanoma cells have receptors (called CXCR3) that respond to CXCL10; so the researchers theorized that by shutting down the CXCL10 signaling, it would also inhibit the melanoma moving into the brain.
Using genetic manipulation, the team was able to knock out those CXCR3 receptors in the melanoma cells. The result was that they were successful in blocking the melanoma cells from responding to that CXCL10 signal. Basically, the CXCL10 activated those inflammatory pathways, but the melanoma was no longer able to hitch a ride into the brain to wreak havoc there. Or as the researchers from Tel Aviv University said more formally, “The development of brain metastases was significantly inhibited.”
While the team used mice models to investigate, the fact that humans also produce CXCL10 and human melanoma cells produce CXCR3 shows potential payoffs with this line of inquiry. As the lead author of the study, Professor Neta Erez of the Department of Pathology at Tel Aviv University Sackler Faculty of Medicine, stated, “Our findings suggest that blocking this signaling pathway may prevent brain metastasis. The CXCL10-CXCR3 axis may be a potential therapeutic target for prevention of melanoma brain metastasis.”
Previous research demonstrated that CXCL10 levels are elevated in advanced melanoma patients and were associated with poor clinical outcomes. It’s not a stretch to say that the CXCL10-CXCR3 axis may hold the key to preventing melanoma from metastasizing to the brains of future melanoma patients.