Scientists Identify Potential New Target for Treating Metastatic Cancer

By Jason Socrates Bardi

A team of scientists at The Scripps Research Institute have identified a human protein that may be a new target for future cancer therapies. By experimentally blocking the action of this protein, called CD151, the team showed they could stop cancer cells from metastasizing, or spreading from one tumor to establish new tumors elsewhere.

Metastasis is a hallmark of late-stage cancer and contributes significantly to the large number of cancer deaths each year in the United States. In the cover article of the March 11 issue of the journal Cancer Cell, Scripps Research Professor James Quigley and his colleagues describe how blocking CD151 stopped the spread of human cancer cells within fertilized chicken embryos—an experimental model used for studying cancer metastasis.

"Targeting this protein keeps the cancer cells tied to their tumors," says Quigley. "This may be the first time anyone has shown a potential way of blocking cancer metastasis at its very earliest stage—as the cells are first pulling away from their tumors of origin."

While these results provide only a proof of concept, they suggest it may be possible to design new ways of fighting cancer by treating people with drugs that block CD151. Any new cancer treatments based on this discovery would likely take years to develop and would have to prove effective in numerous preclinical experiments and in human safety and efficacy trials before finding their way into the clinic.

A Profound Need

The need for more effective cancer treatments is profound. More than half a million people a year die from cancer in the United States alone, making it the second-leading cause of death in this country.

Caused by DNA mutations within a cell that disrupts its programming and cause it to begin dividing, cancer can be pernicious. Over time, one cell on a tissue within the body can grow into a large cluster of cells, forming a tumor that may severely interfere with the function of that tissue. Doctors can remove tumors by treating them with drugs, bombarding them with radiation, or excising them surgically, but these treatments often fail, ultimately because the tumor cells don't stay put. Instead they metastasize—separating from the primary tumor and establishing a new focus of cancer cells elsewhere in the body.

When cancer cells metastasize, they must accomplish a sequential series of feats in order to successfully establish new tumors. First, they have to break free, enter the bloodstream, survive in the circulation, come to a halt somewhere else in the body, invade a new tissue, establish a new tumor, and find a way of supplying themselves with blood and nutrients as they divide and grow into a new colony.

Cancer researchers have long focused on the fact that as cancer cells makes this journey, they interact with a changing environment by altering the expression of their genes and changing the assortment of proteins on their surfaces.

Interfering with these proteins is a proven way of blocking metastasis, but much of the research to date has focused on targeting those proteins involved in the later stages of the metastasic journey—the ones that help the cells enter the bloodstream, migrate, or form new blood supply lines to feed a growing tumor, for instance. Researchers have never found a way to target a protein and block a tumor cell from detaching in the first place.

Now, Quigley and his colleagues have shown for the first time that they can block tumor cell detachment and halt metastasis by targeting CD151.

Unexpected Results

The work started several years ago, when Quigley and his colleagues generated a unique antibody in mice that blocked metastasis. The antibody, as it turned out, targets CD151, a protein that sits in the cell membrane and had been associated with cell motility—the ability of cells to crawl. So, Quigley and his colleagues initially assumed that the antibody would stop metastasis by preventing cancer cells from crawling. They were surprised to discover how it actually worked.

The scientists used an experimental system with fertilized chicken embryos with no shells. These embryos develop blood vessels when left in an incubator for several days, and cancer cells from metastatic tumors implanted into them will readily migrate through these blood vessels to form new tumor colonies in under a week. When Quigley and his colleagues treated the embryos with the antibodies, however, they found that the tumors did not metastasize. Instead, the cancer cells stayed tightly clustered.

It turns out that the antibody does not block motility at all. It halts "intravasation"—the moment when a cancer cell breaks free from its tumor. Somehow the antibody prevents the interaction that allows the cell to release itself. Under the microscope, these cells can be seen in real time, trying to crawl away from the tumor mass only to snap back every time. The cells can crawl perfectly, but they are tied to their tumor.

The exact mechanism of this tethering is unclear, but the principle is clear enough. Without the antibodies, the cancer cells rapidly escape into the embryo vasculature and establish new tumors elsewhere.

In addition to Quigley, the article: "The inhibition of tumor cell intravasation and subsequent metastasis through the regulation of in vivo tumor cell motility by the tetraspanin CD151" was authored by Andries Zijlstra, John Lewis, and Heidi Stuhlmann formally at The Scripps Research Institute and Bernard DeGryse of FIRC Institute of Molecular Oncology in Milan, Italy. It appears in the March 11, 2008 issue of the journal Cancer Cell.

Support for this work was provided by grants from the National Institutes of Health.

Send comments to: mikaono[at]scripps.edu

"Targeting this protein [CD151] keeps the cancer cells tied to their tumors," says Professor James Quigley, who led the recent study. Photo by Kevin Fung.