Conventional biological wisdom holds that living cells interact with their environment through an elaborate network of chemical signals. As a result many therapies for the treatment of cancer and other diseases in which cell behavior goes awry focus on drugs that block or disrupt harmful chemical signals. Now, a new road for future therapies may have been opened with scientific evidence for a never seen before way in which cells can also sense and respond to physical forces.
A team of researchers with the Lawrence Berkeley National Laboratory (Berkeley Lab) and the University of California (UC) Berkeley 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.
''This 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,'' says chemist 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.''
|Jay Groves (foreground) and Pradeep Nair used TIRF imaging and their own spatial mutation strategy to discover a new way in which cells can sense and respond to physical forces. (Photo by Roy Kaltschmidt, Berkeley Lab Public Affairs)|
Groves holds a joint appointment with Berkeley Lab's Physical Biosciences Division and UC Berkeley's Chemistry Department. He is also a Howard Hughes Medical Institute (HHMI) investigator. With members of his research group Khalid Salaita and Pradeep Nair, plus Rebecca Petit, he has co-authored a paper on this research that was published in the March 12, 2010 issue of the journal Science. The paper is titled, Restriction of Receptor Movement Alters Cellular Response: Physical Force Sensing by EphA2. Other co-authors were Joe Gray, Richard Neve and Debopriya Das of Berkeley Lab's Life Sciences Division.
Cancer and EphA2/ephrin-A1
The term ''metastasis'' comes from the Greek word for ''displacement,'' and it is used to describe the process whereby cancer cells detach from a tumor, enter the bloodstream and spread to other tissues throughout the body. For example, cancerous breast cells can spread to a lung and form a new breast cancer tumor there. Central to metastasis is the EphA2/ephrin-A1 receptor-ligand complex.
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.