Melanoma skin cancer metastases reach the brain by 'impersonating' normal cells of the immune system

Researchers at Tel Aviv University succeeded in developing a method to neutralize the mechanism, which may in the future block the pathway and prevent brain metastases in melanoma patients * The article was recently published in the journal Cell Reports

Researchers at Tel Aviv University, led by Prof. Neta Erez, Dr. Hila Doron and research student Malek Amer from the Department of Pathology at the School of Medicine, discovered that metastases of the violent melanoma skin cancer reach the brain by 'cheating' the immune system: they 'disguise themselves' ' to the cells of the immune system itself, which are mobilized to fight simulated tissue damage in the brain, and reach the brain through the seemingly normal pathway that was opened for those cells. In addition, the researchers developed a method to neutralize the sophisticated fraud mechanism, which may prevent the development of brain metastases in melanoma patients in the future.

The research was carried out in collaboration with Prof. Ronit Sachi-Painero, Head of the Laboratory for Cancer Research and Nanotechnology, Department of Physiology and Pharmacology, Faculty of Medicine at Tel Aviv University.

The article was recently published in the journal Cell Reports.

"Melanoma skin cancer is known as a violent and deadly disease, mainly because it metastasizes to vital organs in the body, and in many cases to the brain," says Prof. Erez, who serves as the head of the pathology department at the School of Medicine, "We wanted to find out how the cancer cells overcome the brain's natural defenses , and penetrate into it in order to create metastases.

"Based on previous studies in our laboratory, we focused on cells of brain tissue called astrocytes, which are found, among other things, in the blood-brain barrier, and whose role is to maintain the normal structure of the brain, Prof. Erez notes, "It is known that in the event of damage to the brain tissue, the astrocytes secrete substances defined as inflammatory factors , which signal inflammatory cells of the immune system throughout the body and call them to reach the brain. The inflammatory cells receive the message through specific receptors for those inflammatory factors, and sense to the brain in a dedicated route opened for them, to extend help. We tested a possible link between this essential mechanism and the metastatic mechanism of melanoma."

As part of the study, the researchers examined mice in a melanoma model, as well as tissues from melanoma metastases in the human brain, which were surgically removed in an effort to save the patients' lives. First, they isolated astrocytes from brain tissue, and performed molecular characterization on them. They found a significant increase - compared to normal values ​​- in the production of inflammatory factors in general, including a particularly large increase in the production of a factor known as CXCL10. In addition, they performed a dedicated staining of the brain tissue sections, in order to locate astrocytes in them alongside the inflammatory factors they secrete. In this way, they found that the astrocytes become active and secrete inflammatory factors already at the beginning of the disease - when the melanoma is in the stage of initial growth on the skin, before the metastases are established. (In another study, the researchers are now examining how melanoma, already in its initial stages, causes this phenomenon in the brain).

Now the researchers examined the melanoma cells, and found that in some of them a receptor for the inflammatory factor CXCL10 launched by the astrocytes is activated - exactly the same as the receptor in the inflammatory cells of the immune system. In other words, the cancer cells pick up the inflammatory factor, and respond to the call that was actually intended for the cells of the immune system. This is how they actually 'cheat' the immune system, and use its normal pathway to reach the brain and penetrate it.

"After we discovered the mechanism, we wanted to find out if there was a way to block it and stop the metastatic process," says Prof. Erez. "Using genetic methods, we neutralized the receptor for the CXCL10 factor in the melanoma cells, so that they could not recognize it and respond to the call of the astrocytes." The results were promising: in mice in which the receptor was neutralized, far fewer brain metastases developed, compared to mice in the control group, in which the receptor continued to function.

"In our research we uncovered a sophisticated mechanism by which melanoma skin cancer cells manage to trick the immune system, penetrate the brain and produce metastases," concludes Prof. Erez. "Also, we found a way to block the mechanism through genetic means, by neutralizing the receptor that the melanoma cells develop for an inflammatory factor that is sent from the brain to the cells of the immune system. We believe that these discoveries may form the basis for the development of effective treatments that will prevent the development of brain metastases in melanoma patients in the future."

for the scientific article

More of the topic in Hayadan:

• Researchers have grown a human blood-brain barrier outside the body, in a way that makes it possible to predict the penetration of drugs into the brain in a customized way 
• Breaking the barrier to the brain / Janine Inter Landi
• Two genes responsible for the development of brain metastases among lung cancer patients have been identified