New technique finds molecules necessary for cancer metastasis

Provides unique drug targets to prevent spread

Tufts University researchers have identified several proteins on the surface of cancer cells that contribute to the cells’ ability to metastasize. When the researchers destroyed these particular proteins, the cancerous cells show a significant decrease in their ability to invade healthy cells – a finding that provides a new target for badly needed drugs. Although most cancer deaths occur from metastasis, not from the original cancer itself, no drug treatments are currently available specifically to prevent the spread of the cancer from the original site to other organs. The team also has discovered new roles related to the spread of cancer in two molecules known for other, non-cancer activities.

Dr. Daniel Jay presented the study on Sunday, April 3, at Experimental Biology 2005 in San Diego, as part of the scientific sessions of the American Society for Biochemistry and Molecular Biology.

The findings were made possible, says Dr. Jay, because he and his colleagues have developed a new Fluorform-Assisted Light Inactivation technology (FALI) that is a new generation of the Chromophore-Assisted Laser Inactivation (CALI) technique he created 17 years ago to inactivate specific proteins in living cells at precise times and locations. The researchers are able to destroy a specific protein, sparing all other proteins attached to the cell as well as the cell itself, by targeting the antibody to that specific cell. They tag the antibody with a dye that absorbs a specific wavelength of light. When the light is turned on (earlier technology required lasers; the new FALI technology needs only the light of a slide projector), the light energy absorbed by the dye in the antibody generates free radicals that destroy the specific protein bound by that antibody.

What gives the new FALI approach its power, says Dr. Jay, is its high throughput and its ability to couple with the large antibody libraries now available. Whereas the team used to look at one protein at a time, it now can rapidly scan thousands of the proteins associated with cancer cells, systematically “knocking out” one at a time and looking for those whose absence on the cell causes a significant decrease in invasiveness.

At the Experimental Biology 2005, Dr. Jay also describes two of the molecules identified by the FALI approach to have large implications for metastasis. Both were well known to scientists, but the Jay team is the first to recognize the roles they play in cancer. The first molecule, HSP90A, is a molecular chaperone that facilities the folding and activation of different proteins within the cells. The Jay laboratory was the first to recognize HSP90A also had a role outside the cell; it activates a particular matrix metalloprotease required for restructuring the surrounding matrix as cells move and invade.

The second molecule, the polio virus receptor CD155, has been recognized for decades as the pathway by which the polio virus is able to enter motor neurons in the nervous system. Dr. Jay and his team have found that the receptor also plays a role in how brain tumor cells move in the brain, spreading to healthy cells.

“Our current interest is cell motility related to the spread of cancer,” says Dr. Jay, “but the speed and sensitivity of the FALI approach gives it wide applicability as a method to identify functionally important proteins in a variety of disease processes.”

Coauthors of the presentation are Brenda Eustace, Takashi Sakurai, and Kevin Sloan. Funding for the study came from the National Cancer Institute and the Goldhirsh Foundation.