The research findings, recently published in the online edition of the scientific journal Nature Cell Biology, contribute to the understanding of how cancer metastases form, and they may be used, in the future, as a basis for developing methods to cure the disease
The stage at which a primary cancerous tumor begins to metastasize is one of the main factors affecting the violence of the tumor, the degree of damage it causes, and the chances of recovery from the disease. The ability to form metastases is related to a feature that characterizes both healthy and cancerous cells: the ability to migrate from place to place, that is, to move from a fixed state to a mobile state. A team of scientists from the Weizmann Institute of Science is currently revealing new details about the molecular mechanism responsible for migration. The research findings, recently published in the online edition of the scientific journal Nature Cell Biology, contribute to the understanding of how cancer metastases form, and they may be used, in the future, as a basis for developing methods to cure the disease.
Movement of cells through the blood vessels and lymphatic vessels takes place as part of natural biological processes (such as wound healing), and also in cancerous processes. For this migration to be possible, the cell must detach from the cells surrounding it and from the intercellular material to which it is anchored. The signaling that instructs the cell to prepare for migration is done through certain substances that reach the cell from the outside, called "growth factors". Besides controlling the cell's ability to move, these substances activate many other cellular processes such as division and differentiation, and their abnormal activity is involved in various types of cancer. When the growth factor binds to its receptor, it generates a series of structural changes in the cell - the cellular skeleton, the "scaffolding system" of the cell, made of dense and ordered protein fibers, breaks down, which activates various mechanisms that allow the cell to move and migrate. An intermediate step in the process of the effect of the growth factor is a reduction in the production rate of certain proteins, which occurs at the same time as an increase in the production of other proteins, which carry out the processes necessary to start the process of cell migration.
In order to try and understand which are the proteins that mediate the activity of the growth factor, and which are the genetic mechanisms that activate the process, a large team of researchers headed by Prof. Yosef Jordan from the Department of Biological Control at the Weizmann Institute of Science, which included a student
Continue on the next page >>>
>>> Continue from the previous page
- 2 -
The research Dr. Menachem Katz and other members of Prof. Jordan's research group, who was assisted by other research students from the group of Prof. Eitan Domani from the Department of Physics of Complex Systems at the Weizmann Institute of Science, and Prof. Gideon Ravavi from the Haim Sheba Medical Center in Tel Hashomer. In the first step, the scientists mapped all the genetic changes that occur in the cell in response to the administration of a growth factor, which encourages the development of breast cancer metastases. Within the huge collection of data that was obtained, which includes all the proteins whose quantity increases or decreases, a family of proteins called "tensins" stood out, whose role is to stabilize the cell structure. To the researchers' surprise, the amount of one of the family's proteins increased dramatically, while the level of another protein decreased. What is the reason for the opposite reaction of similar proteins, members of the same family?
It turns out that despite the family resemblance between the two proteins, there is a significant structural difference between them. The protein, whose quantity decreases following the administration of a growth factor, is a relatively long molecule, consisting of two arms: one arm binds to the protein fibers that form the cellular skeleton, and another arm binds to anchor points found on the cell membrane, which attach the cell to the extracellular material. This protein stabilizes the cell structure, and attaches it to the extracellular material. The second protein, on the other hand, is shorter, and consists of a single arm that binds only to the anchoring point. When the protein binds to the anchoring points, it forms a kind of "plug" that covers them, preventing them from binding the skeletal fibers. As a result, the cell scaffolds collapse, and the cell begins to move, in a way that may lead it to establish a new metastasis.
A series of experiments, conducted using genetic engineering methods, proved that the growth factor does indeed directly affect the two proteins, both in healthy cells and in breast cancer cells, and that these two proteins control the cells' ability to migrate. Thus, for example, when the researchers prevented the production of the short protein, which creates the "clot", cell migration was prevented, while its overproduction increases migration.
Later, the scientists performed a series of tests on women with inflammatory breast cancer. This type of disseminated and metastatic cancer is known to be extremely violent, and in many cases it causes the early death of the patients. In the past it was found that this type of cancer is associated with increased activity of the growth factor. The researchers discovered that there is a high correlation between overactivity of the growth factor in cancer patients, and high levels of the "cork protein" responsible for cell migration. It also turned out that the binding of the growth factor to its receptor increases the amount of the "cork protein". In addition, the researchers found a correlation between high levels of the "cork protein" and the appearance of cancerous metastases in the ligaments
Continue on the next page >>>
>>> Continue from the previous page
- 3 -
the lymph. This discovery supports the hypothesis that this protein plays an important role in the formation of cancer metastases, since the lymph nodes are the first stop for the cancer cells carried in the lymph vessels from the primary tumor site to the rest of the body.
In another experiment, the scientists tested the effect of a drug that blocks the receptor for the growth factor, which is used to treat breast cancer patients who show excessive activity of the growth factor. An examination of patients who received the drug showed that the treatment causes the dangerous protein to disappear from the cancer cells. Prof. Jordan: "We have identified a clinically important mechanism that can predict the development of cancer metastases, and possibly also the response to treatment." The discovery of the mechanism may contribute, in the future, to the development of a drug that will prevent or reduce the production of the protein, thus preventing the formation of metastases in breast cancer and other types of metastatic cancer.
Dr. Menachem Katz, Dr. Ido Amit, Dr. Ami Tsari, Sarah Lavi, Nir Ben-Shetrit, Gabi Tretzik, Dr. Moshit Lindzen and Roy Avraham from the research group of Prof. Yosef Yordan participated in the study; Tal Shay from Prof. Eitan Domani's research group; Dr. Ninet Amarilio and Dr. Yasmin Yaacov-Hirsh from the research group of Prof. Gideon Ravavi at Sheba Hospital in Tel Hashomer; A team of researchers from the Institute of Molecular Pathology and Immunology and the Faculty of Medicine at the University of Porto, Portugal; and American researchers from the University of Davis, California, Boston University, and Duke University, North Carolina.
