A protective protein, which was generally known to be effective against blood clots, was found to be capable of inhibiting the most violent means of cancer in the human body - metastasis. Prof. Tal Borshtin-Cohen, the leader of the research, believes that the surprising discovery explains why there are quite a few anti-cancer treatments that fail: "The understanding that protein S helps the body fight metastases is a warning light for anti-cancer treatments, which are designed to inhibit this protein's pathway"
Prof. Tal Borshtin-Cohen from the Faculty of Dentistry at the Hebrew University and her research team have been investigating the diverse actions of a protein called "Protein S" for a long time. The protein is known as an anticoagulant in the blood, and is largely responsible for the fact that the blood flowing in our arteries remains liquid and does not clot. Despite the deep familiarity of many researchers with this property of the protein, few in Israel and in the world understand that protein S has additional and no less important properties that maintain a healthy balance in our bodies.
Prof. Borshtin-Cohen's laboratory team sees this as a particularly important scientific challenge, and tries to understand and decipher the hidden functions of the protein, in order to reveal new aspects that we did not know about. As part of a previous study, the team realized that the protein is more strongly expressed in cancer cells, where the researchers discovered that it encourages violent properties in cancer cells. But to the surprise of Prof. Borshtin-Cohen and her team, the results of new work revealed that the same protein - when secreted from immune cells - has a completely opposite activity.
This is the first significant study ever performed on protein S in a cancer context and not in the context of hypercoagulability. The research team's initial hypothesis was that immune cells that infiltrate cancerous tumors to fight them bring with them more protein S, thus contributing to the growth of the cancerous tumor and its metastases. Amazingly, the researchers found that protein S in immune cells has the opposite role to that in cancer cells: while in cancer cells the protein encourages violence and contributes to the progression of cancer, the immune cell is actually important for suppressing cancer metastases, thus actually protecting our bodies from those metastases. Cancer is very deadly when it metastasizes, and it is very difficult to cure it at this stage.
Most cancer patients die from metastases
"Most cancer patients do not die from the primary tumor but from the metastases, therefore finding a protein and mechanism of action in immune cells that protects against metastases is a groundbreaking finding," explained Prof. Borshtin-Cohen this week. The surprising research results were published this month in a scientific article in The Journal of Clinical Investigation, one of the most prestigious journals in the world for research leading from the laboratory to clinical applications.
The results of the study revealed that the presence of protein S in immune cells reduced the average size of metastases in metastatic breast cancer by 3.3 times, and by 2.2 times in metastatic lung cancer. In lung cancer, the presence of the protein even reduced the average number of metastases in the lungs by 3.6 times, compared to the experimental mice that did not express the protein in the immune cells. The tests also revealed that the protein plays an important role in regulating and controlling the inflammatory response, which indirectly dictates the development of metastases. Thus, the researchers found that protein S suppresses inflammation in macrophage cells - the immune cells, and in its absence, the macrophages secrete inflammatory substances in the body, and in particular the lungs - a favorite organ for many cancers to metastasize. The effect of the protein from the macrophages on the lungs was so significant that a bone marrow transplant (the source tissue for macrophage cells) of a control mouse expressing the protein eliminated the lung inflammation of the experimental mouse and reduced the number of metastases, and vice versa, that is, a bone marrow transplant of the experimental mouse induced inflammation healthy control mice, and correspondingly caused a greater metastatic burden indicating a more severe disease. "These findings show that the anti-inflammatory properties of protein S are important for the control and control of inflammation, not only in the blood but also in the organs of the body, and in physiological conditions and diseases in which inflammation is involved," the researchers explain.
A molecular switch
"You can say that we have found a molecular switch that dictates whether there will be many large metastases or not. The results are very encouraging, and now we must take into account all the side effects that may be caused by manipulating this protein - so that there is no accidental and unwanted damage. It is a very complex and challenging protein, but there is no doubt that the beginning of the road in understanding its functions outside the coagulation system is promising. What is clear to us today is that although in cancer cells this protein is likened to oil for the cancerous fire, as far as macrophages are concerned - it is a metastasis-inhibiting protein," Prof. Borstein-Cohen concluded, adding that "the understanding that protein S helps the body fight metastasis is a warning light for anti-cancer treatments, which aim inhibit the protein's pathway, and may explain why some treatments against cancer fail, since they neutralize, among other things, the protective action of the protein."
The future, according to the researcher, is promising: "We are now working on understanding the great complexity of how protein S works, in order to direct its activity in the anti-cancer direction in order to prevent and make it difficult for metastases to develop, a situation in which the body may lose. I hope that the results of our research will have life-saving consequences."
The research, led by Prof. Borshtin-Cohen, who heads the Laboratory for Developmental Biology and Cancer Research at the Faculty of Dentistry, was made possible thanks to international and intra-university cooperation, and was funded by the Israel Cancer Research Fund (ICRF) and the Cancer Society.
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