Weizmann Institute scientists discover a control mechanism for metastasis

[gdpawel]

A "growth factor" is about twenty small proteins that attach to specific receptors on the surface of stem cells in bone marrow and promote differentiation and maturation of these cells into morphotic constituents of blood. And blood is a circulating tissue composed of fluid plasma and cells (red blood cells, white blood cells, platelets). Problems with blood composition or circulation can lead to downstream tissue (which is made up of cells) dysfunction. If pharmaceutical EPO stimulates the bone marrow to make red blood cells, it could feed the growth of tumors in cancer patients.

A metastasis occurs when cancer cells dissociate from the original tumor and migrate via the blood stream to colonize distant organs. This is the main cause of cancer death. For a cell such as a cancer cell to migrate, it first must detach itself from neighboring cells and the intercellular material to which it is anchored. Before it can do this, it receives a signal from outside the cell. This signal takes the form of a substance called a growth factor, which, in addition to controlling movement, can activate a number of processes in the cell including division and differentiation.

The growth factor attaches to a receptor on the cell wall, 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, a number of protein levels change: some get produced in higher quantities and some in less.

To understand which proteins are modulated by the growth factor and the nature of the genetic mechanisms involved in cancer cell migration, a map is needed all of the genetic changes that take place in the cell after the growth factor signal is received. One family of proteins stands out. Tensins are proteins that stabilize the cell structure. The amounts of one family member rise dramatically while, at the same time, the levels of another drop.

Despite a familial similarity, there is a significant difference between them. 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. This action is what stabilizes the cell's structure. The protein that increases, on the other hand, is made up of one short arm that only attaches to the anchor point on the cell membrane. Rather than 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, scientists have showed that the growth factor directly influences levels of both proteins, and that these, in turn, control 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.

Scientists at The Weizmann Institute of Science, Rehovot, Israel, carried out tests on tumor samples taken from around 300 patients with inflammatory breast cancer, a rare but swift and deadly form of the disease, which is associated 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, in turn, were associated with cancer metastasis to the lymph nodes -- the first station of migrating cancer cells as they spread to other parts of the body.

In another experiment, the scientists examined the effects of drugs that block the growth factor receptors on the cell walls. In patients who received these drugs, the harmful 'plug' proteins had disappeared from the cancer cells. The mechanism can predict the development of metastasis and possibly how the cancer will respond to treatment. This discovery may, in the future, 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.

Source: Weizmann Institute of Science