Cutaneous melanoma is the deadliest of all skin cancers, especially due to its tendency to invade and develop metastases at distant sites. It is the third primary malignancy after lung and breast cancers that preferentially colonizes the brain, with an incidence of brain metastasis development.
For the first time, scientists from Tel Aviv University unraveled a mechanism that enables skin cancer to metastasize to the brain and managed to delay the spread of the disease by 60% to 80% using existing treatments. They found that The cancer cells “recruit” astrocytes, star-shaped cells located in the spinal cord and brain that are in charge of maintaining homeostasis, or stable conditions, in the brain, in melanoma patients with brain metastases.
Prof. Ronit Satchi-Fainaro said, “In an advanced stage, 90% of melanoma (skin cancer) patients will develop brain metastases. This is a puzzling statistic. We expect to see metastases in the lungs and liver, but the brain is supposed to be a protected organ. The blood-brain barrier keeps harmful substances from entering the brain, and here it supposedly doesn’t do the job—cancer cells from the skin circulate in the blood and manage to reach the brain. We asked ourselves with ‘whom’ the cancer cells’ talk’ to in the brain to infiltrate it.”
Prof. Satchi-Fainaro said, “The astrocytes are the first to come to correct the situation in the event of a stroke or trauma, for example, and it is with them that the cancer cells interact, exchanging molecules and corrupting them. Moreover, the cancer cells recruit the astrocytes so that they do not inhibit the spread of the metastases. As such, they create local inflammation in the melanoma cells-astrocytes interaction areas that increase the permeability through the blood-brain barrier and the division and migration of the cancer cells.”
“The communication between them is reflected in the fact that the astrocytes begin to secrete a protein that promotes inflammation called MCP-1 (also known as CCL2), and in response to this, the cancer cells begin to express its receptors CCR2 and CCR4, which we suspected to be responsible for the destructive communication with the astrocytes.”
Scientists tested their hypothesis by inhibiting the expression of the protein and its receptors in genetically-engineered lab models and 3D models of primary melanoma and brain metastases. They used both an antibody (biological molecule) and a small molecule (synthetic) designed to block the MCP-1 protein.
They also employed CRISPR technology to genetically edit the cancer cells and cut out the two genes that express the two relevant receptors, CCR2 and CCR4. With each method, the researchers could delay the spread of metastases.
Prof. Satchi-Fainaro said, “These treatments succeeded in delaying the penetration of the cancer cells into the brain and their subsequent spread throughout the brain. It’s important to note that melanoma metastases in the brain are very aggressive, with a poor prognosis of 15 months following surgery, radiation, and chemotherapy. Depending on the intervention stage, we reached a 60% to 80% delay.”
“We achieved the best results with the treatment conducted immediately after surgery to remove the primary melanoma, and we were able to prevent the metastases from penetrating the brain; therefore, I believe that the treatment is suitable for the clinic as a preventive measure.”
“Both the antibody and the small molecule we used—primarily intended to treat sclerosis, diabetes, liver fibrosis, and cardiovascular diseases, as well as serve as a biomarker for other types of cancer—have already been tested on humans as part of clinical trials. Therefore, these treatments are safe, and we can try repurposing them for melanoma.”
- Sabina Pozzi, Anna Scomparin et al. MCP-1/CCR2 axis inhibition sensitizes the brain microenvironment against melanoma brain metastasis progression. JCI Insight. DOI: 10.1172/jci.insight.154804