New Synthetic Form of Protein Holds Promise to Stop Cancer Spread

Researchers at the Medical College of Wisconsin in Milwaukee have a pending patent on a new synthetic form of a protein involved in certain types of cancers and immune system diseases.

The protein, CXCL12, is known as a chemokine. Chemokines are proteins that regulate the movement of cells into tissues and recruit infection-fighting white blood cells to infected and injured sites. They essentially act as homing beacons for the immune system.

New information on the structure of the protein was discovered in the lab of Brian Volkman, Ph.D., associate professor of biochemistry at the Medical College. The findings were based on seminal reports by Michael Dwinell, Ph.D., associate professor of microbiology and molecular genetics, who initially inspired Dr. Volkman to look into the properties of CXCL12 in 2001.

“We hope that stable synthetic versions of CXCL12 will allow us to conduct proof-of-concept studies about cancer prevention,” Dr. Volkman says. “It’s clear that CXCL12 is an important molecule for designing new ways to treat cancer.”

The new findings from the Medical College are published in the September issue of Science Signaling, a new online journal published by Science magazine. Christopher Veldkamp, Ph.D., a biochemistry graduate of the Medical College’s Graduate School of Biomedical Sciences, who was awarded a postdoctoral research fellowship by the American Cancer Society earlier this year, is lead author of the study.

It had been previously established that CXCL12 and its target cellular receptor, CXCR4, played an important role in the migration of cancer cells to common sites of tumor formation, such as bone marrow, lymph nodes, liver and lung tissue. Dr. Dwinell’s laboratory established that CXCL12 expression was key to interfering with the progression of cancer.

To discover the new inhibitor, Dr. Volkman’s lab created a new three-dimensional model of how the CXCL12 protein interacts with a portion of the CXCR4 receptor. Because previous research on the CXCL12 structure failed to resolve these details, a key step in the spread of metastatic cancer remained poorly understood.

To complete the molecular model for CXCL12 binding to CXCR4, Drs. Volkman and Veldkamp discovered that it was necessary to link two CXCL12 molecules, in effect locking it into a form that could not be chemically separated. This locked form of the protein, known as a dimer, could still bind to the CXCR4 receptor.

However, the locked protein displayed different behavior than the unlocked form. A normal CXCL12 protein strongly induces cell migration, but the locked form of the protein caused no cells to migrate at all.

The researchers then ran another experiment to see what would happen if the normal CXCL12 and locked CXCL12 dimer were combined. The combined molecule had the opposite effect of the single molecule, and it resulted in a near elimination of cell migration. This meant they had discovered that it was possible to convert CXCL12 into a protein that inhibits cell migration.