Discovery of key molecular step which allows cancer cells to move to different parts of the body

Researchers at The University of Texas M. D. Anderson Cancer Center have figured out a key molecular step by which a cancer cell can unhook itself from the mesh weave of other cancer cells in a tumor, and move away to a different part of the body - the process, known as metastasis, that makes cancer so dangerous.

Describing what they call a critical "molecular switch" - detailed in the advance online edition of the journal Nature Cell Biology - the researchers say the door is now open to designing new ways to block that metastasis.

"It always has been a mystery as to what allows a cancer cell to become mobile and move away from a tumor, but now we have found a very interesting mechanism that explains it," says the study's lead author, Mien-Chie Hung, Ph.D., a professor and chair of the Department of Molecular and Cellular Oncology.

That switch, in the form of an enzyme known as GSK-3ß, which is known to alter the function of proteins, may "offer us an anticancer strategy to pursue," Hung says.

Most cancers are of the "solid tumor" variety, and are made up of epithelial cells - those which make up the membranous tissue covering organs and other internal surfaces of the body. Although epithelial cells are firmly fixed to each other in a network that makes up tissue, researchers know from the study of developmental biology that embryonic epithelial cells have the ability to move.

To do that, epithelial cells take on the characteristics of what are known as "mesenchymal" cells, those that develop into connective tissue and blood vessel cells, among other tissue types. They are capable of forming collagen fibers that allows them to "creep along" to where they are needed during development.

This process, known as "epithelial-mesenchymal transition (EMT)," has recently been observed in cancer progression, Hung says. "It was discovered that the increased motility and invasiveness of cancer cells resembles the EMT that occurs during embryonic development," he says. "And since about 90 percent of cancer deaths result from local invasion and distant metastasis of tumor cells, an insight into how this process works in cancer has been urgently needed."

Some of this transition process in cancer cells already has been described, Hung says. What has been known is that epithelial cells have a lot of protein known as E-cadherin, which act like anchors, fixing the cells onto the tissue membrane while gluing cells to each other. In contrast, mesenchymal cells do not "express" E-cadherin, which allows them to move freely.

Another piece of the puzzle was already in place: a transcription factor known as "snail" was found to control the gene that produces the E-cadherin protein. Snail turns off E-cadherin expression, thus freeing epithelial cell from its tethers. So the question Hung and his research team explored is: what regulates snail? What "tells" snail to turn off E-cadherin? "Cells without E-cadherin are not stuck to each other any more and can move, so we looked for the regulator of snail," Hung says.

Through a series of experiments, they found that the GSK-3ß enzyme controls snail. It does this by directing snail out of the cell's nucleus (where proteins are located) and into the cell's cytoplasm, where it is then degraded. "This enzyme tells the snail transcription factor to go to the wrong place, where it is then destroyed," Hung says.

So when GSK-3ß controls the action of snail, a cancer cell continues to produce E-cadherin and retains all the properties of a fixed epithelial cell, the researchers discovered. Tumor cells in which GSK-3ß activity is repressed become unanchored, Hung says, suggesting that a therapy that bolsters GSK-3ß may repress the ability of cancer to spread.

Hung and his group also say that known cancer pathways, such as those that involve the epidermal growth factor receptor (EGFR) have been shown to inhibit the GSK-3ß enzyme. "So this all makes sense. We have mechanistically shown how a signaling pathway known to promote cancer development can also promote metastasis," he says. "Now we have to work on ways to inhibit that process."