Researchers from Tel Aviv University have, for the first time, discovered a mechanism by which skin cancer can spread to the brain and were able to delay the spread of the disease by 60% to 80% using current treatments. The encouraging study was led by Professor Ronit Sachi Finaru and Ph.D. Student Sabina Pozzi of the Sackler School of Medicine at Tel Aviv University. The results were published in the scientific journal JCI Insight.
“At an advanced stage, 90% of melanoma (melanoma) patients develop brain metastases,” explains Professor Sachi-Vinaro. “This is a confusing statistic. We would expect to see metastases in the lungs and liver, but the brain is supposed to be a protected organ. The blood-brain barrier prevents harmful substances from entering the brain, and presumably it doesn’t do the job here — cancer cells from the skin spread into the blood and get to the The brain. We asked ourselves ‘whom’ are the ‘cancer cells’ in the brain talking to to infiltrate.’
Researchers from Tel Aviv University found that in melanoma patients with brain metastases, cancer cells “recruit” cells called astrocytes, which are star-shaped cells found in the spinal cord and brain that are responsible for homeostasis, or maintaining a steady state, in the brain . .
“Astrocytes are the first to come to rectify the situation in the event of a stroke or trauma, for example, and cancer cells interact with them, exchanging and degrading molecules. Moreover, cancer cells recruit astrocytes so that they do not prevent the spread of metastases,” says Prof. Sachi Vainaro. , thus creating local inflammation in areas of interaction of melanoma cells and astrocytes that increase permeability across the blood-brain barrier, as well as division and migration of tumor cells.The connection between them is reflected in the fact that astrocytes begin to secrete an inflammation-promoting protein called MCP-1 (also known as MCP-1). named CCL2), and in response, cancer cells begin to express their receptors CCR2 and CCR4, which we suspected are responsible for the destructive communication with astrocytes.”
To test their hypothesis, Professor Saatchi-Vinaro and her team attempted to block the expression of the protein and its receptors in genetically modified laboratory models and in 3D models of primary melanoma and brain metastases. To this end, the researchers used both an antibody (a biological molecule) and a small molecule (synthetic), designed to block the MCP-1 protein. They also used CRISPR technology to genetically modify cancer cells and cut off the two genes that express the two related receptors, CCR2 and CCR4. With each of the methods, researchers have been able to delay the spread of metastases.
“These treatments have been successful in delaying the penetration of cancer cells into the brain and their subsequent spread throughout the brain,” says Professor Sachi Vainaru. “It is important to note that brain melanoma metastases are very aggressive with a poor prognosis by 15 months after surgery, radiation and chemotherapy. We reach 60% to 80% delay, depending on the stage of intervention. We achieved the best results from treatment performed immediately after surgery. To remove the primary melanoma, and we were able to prevent the metastases from penetrating the brain, so I think the treatment is appropriate for the clinic as a preventive measure.Both the antibody and the small molecule we used – which is mainly intended to treat sclerosis, diabetes, cirrhosis and cardiovascular disease, as well as being used as an indicator Vital for other types of cancer – it has already been tested in humans as part of clinical trials. Therefore, these treatments are considered safe, and we can try to reuse them to treat skin cancer.”
The research was conducted in collaboration with additional scientists and clinicians from Tel Aviv University, including Prof. Adi Berzel, Dr. Asaf Madi, Prof. Iris Barshak, Prof. Eran Berlusson, and Prof. Ina Slutsky. International researchers were also involved in the study, including Professor Eitan Rubin from the US National Institutes of Health (NIH), Professor Henry Brim and Thomas Hyde from Johns Hopkins University, and Professor Helena Florendo from the University of Lisbon.
The study was funded by the European Research Council (ERC), the Skin Cancer Research Alliance (MRA), the Khan Foundation, the Israel Cancer Research Fund (ICRF), and the Israel Science Foundation (ISF).).
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