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Possible Impact of Direct Physical Force on Cancer

A possible new therapeutic avenue may have been opened up with scientific evidence for a never-seen-before way in which cells can sense and respond to physical forces. A team of researchers has shown that the biochemical activity of a cellular protein system, which plays a key role in cancer metastasis, can be altered by the application of a direct physical force. This discovery sheds important new light on how the protein signaling complex known as EphA2/ephrin-A1 contributes to the initiation, growth, and progression of cancerous cells, and also suggests how the activity of cancer cells can be affected by surrounding tissue. EphA2 is a member of the receptor tyrosine kinase (RTK) family of enzymes that are key regulators of cellular processes. The over-expression of EphA2 has been linked to a number of human cancers, including melanoma, lung, colon, and prostate, but is especially prominent in breast cancer. Some 40 percent of all breast cancer patients show an over-abundance of EphA2, with the highest levels found in the most aggressive cancer cells. Ephrin-A1 is a signaling protein that is tethered to the surface of a cell’s outer membrane. It binds to EphA2 in a neighboring cell like a key fitted into a lock. When ephrin-A1 binds with EphA2, the newly bound complexes become activated and gather in a cluster. “The host cell will then literally give the clusters a distinctive tug, applying a force that pulls the clusters across the surface of the cell to a centralized location,” Dr. Groves said. “What we found is that by applying an opposing force, we could alter the cell’s biochemical activity. When we applied a big opposing force we were able to convert highly invasive cells into well-behaved cells. This shows that, in addition to chemically sensing the presence of ephrin-A1, the cells also sense the mechanical properties of the local environment in which ephrin-A1 is displayed.”

“This [is the] first evidence that the EphA2/ephrin-A1 receptor-ligand complex, which was previously thought to be strictly a chemical sensor, can actually sense mechanical properties as well,” said chemist Dr. Jay Groves, who led this research. “This coupling of mechanical and chemical signaling, which could never have been seen with classical biological methods, helps explain some of the biological mysteries concerning the onset and progression of cancer.”

Previous observations had indicated that mammalian cells are sensitive to the physical aspects of their environment, such as the texture or geometry of the surrounding tissue. However, evidence that physical forces impact freely-moving signaling molecules (as opposed to focal adhesion molecules) in the membranes of cells has been lacking because the cell membrane is an environment that has always been difficult to characterize and manipulate.

Dr. Groves and his research group have found a way to overcome this obstacle with the development of unique synthetic membranes constructed of lipids and assembled onto a substrate of solid silica that enables them to directly control cellular signaling activities. “We call this approach the ‘spatial mutation’ strategy because molecules in a cell can be spatially re-arranged without altering the cell in any other way,” Dr. Groves said.

“It’s possible that the force-sensing process itself could provide a target for therapeutic intervention,” says Dr. Groves. “We’re also excited about finding targets for which there may be drugs that have already been developed but are now being used to treat diseases other than cancer. Given the sensitivity to mechanical forces displayed by the EphA2/ephrin-A1 signaling complexes, it is possible these existing drugs could be redirected to the treatment of cancer.”

The research was published in the March 12, 2010 issue of Science. [Press release] [Science abstract]