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A metastasis occurs when cancer cells dissoicate from the original tumor and migrate via the blood stream to colonize distant (or even more local) organs. 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. The 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.
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.
Something else happens in regards to signals outside the cell. Endothelial cells, the cells that form the walls of blood vessels, are the source of new blood vessels and have a remarkable ability to divide and migrate. The creation of new blood vessels occurs by a series of sequential steps. An endothelial cell forming the wall of an existing small blood vessel (capillary) becomes activated, secretes enzymes that degrade the extracellular matrix (the surrounding tissue), invades the matrix, and begins dividing. Eventually, strings of new endothelial cells organize into hollow tubes, creating new networks of blood vessels that make tissue growth and repair possible.
Most of the time endothelial cells lie dormant. But when needed, short bursts of blood vessel growth occur in localized parts of tissues. New capillary growth is tightly controlled by a finely tuned balance between factors that activate endothelial cell growth and those that inhibit it.
About 15 proteins are known to activate endothelial cell growth and movement. At a critical point in the growth of a tumor, the tumor sends out signals to the nearby endothelial cells to activate new blood vessel growth (angiogenesis).
Angiogenesis is also related to metastasis. It is generally true that tumors with higher densities of blood vessels are more likely to metastasize and are correlated with poorer clinical outcomes. Also, the shedding of cells from the primary tumor begins only after the tumor has a full network of blood vessels. Both angiogenesis and metastasis require enzymes that break down the surrounding tissue during blood vessel and tumor invasion.
Research has shown that controlling production of new blood vessels can restrict tumor growth, often prolonging the life of the cancer patient. Perhaps the most widely-used anti-angiogenic agent to emerge to date has been the drug Avastin.
And to add into all that mix, anti-cancer treatments often effectively shrink the size of tumors, but some might have an opposite effect (like Taxol) actually expanding the small population of cancer stem cells believed to drive the disease. In other words, some treatments could be producing more cancer stem cells that then are capable of metastasizing, because these cells are tryng to find a way to survive the therapy.
Researchers have recently found that some therapies are not capable of eradicating cancer because they do not target the cancer stem cells responsible for tumor development. So, understanding how to target these markers and these cells could prove useful in treating these cancers.
Anti-tumor and anti-vascular effects were recently studied of various drug agents in fresh biopsy specimens of breast and various other cancers and presented at the American Society of Clinical Oncology Breast Cancer Symposium on September 5, 2008 (see Breast Cancer Symposium 2008 thread).
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