The detailed mechanisms controlling metastasis of breast cancer cells have been discovered by Weizmann Institute of Science researchers in Rehovot. Their findings - just published on-line in Nature Cell Biology - are said to contribute significantly to the understanding of how cancer cells detach from the original tumor and spread via the bloodstream to other parts of the body. In the future their research may help in the development of anti-cancer drugs. "The mechanism we identified is clinically important," said the team leader, Prof. Yosef Yarden of the institute's department of biological regulation. For a cancer cell to migrate, it must first detach itself from neighboring cells and the intercellular material to which it is anchored. Before it can do this, Yarden said, it receives an order from outside the cell - like an officer might tell his soldiers - saying: "Prepare to move." This order comes in the form of a substance called a growth factor, which induces a number of significant other changes in the cell, including cell division and differentiation. The growth factor attaches to a receptor on the cell membrane, initiating a sequence of changes in the cellular structure. The cell's internal skeleton - an assembly of densely packed protein fibers - comes apart, and the protein fibers then form thin threads on the outside of the cell membrane that push the cell away from its neighbors. In addition, the levels of a number of proteins change; some get produced in higher quantities and some in less. Researchers first mapped all the genetic changes that occur in the cell after the growth factor signal is received. As they sifted through the enormous amount of data, including details on every protein level that went up or down, one family of proteins stood out: tensins, which are proteins that stabilize the cell structure. But to the scientists' surprise, the changes were inconsistent. While the amount of one family member rose dramatically, the level of another dropped. The researchers discovered that despite the familial similarity, the two proteins actually had opposite roles. The protein that drops off has two arms. One arm attaches to the protein fibers forming the skeleton, and the other anchors itself to the cell membrane, stabilizing the cell's structure. The protein that increases is made up of one short arm that only attaches to the anchor point on the cell membrane. Rather than offer structural support, this protein acts as a kind of plug, blocking the anchor point and allowing the skeletal protein fibers to unravel into the threads that push the cells apart. The cell is then free to move and, if it's a cancer cell, to metastasize to a new site in the body. In experiments with genetically engineered cells, the scientists showed that the growth factor directly influenced levels of both proteins, and that these controlled the cells' ability to migrate. Blocking production of the short tensin protein kept cells in their place, while overproduction of this protein plug increased their migration. The scientists' next step was to perform tests on tumor samples taken from 300 patients with inflammatory breast cancer, a rare but swift and deadly form of the disease that has been linked with elevated growth factor levels. The scientists found a strong correlation between high growth factor activity and levels of the "plug" protein. High levels of this protein were associated with cancer metastasis to the lymph nodes - the first station for migrating cancer cells as they spread to other parts of the body. In another experiment, the scientists examined the effects of drugs that block growth factor receptors on the cell membrane. In patients who received these drugs, the harmful "plug" proteins had disappeared from the cancer cells. The researchers hope that this discovery may aid in the development of drugs to prevent or reduce the production of the unwanted protein, and thus prevent metastasis in breast or other cancers.