Promising new finding in the fight against cancer metastasis

Dr. John Lewis, in his research lab within the London Regional Cancer Program at LHSC's Victoria Hospital.
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Dr. John Lewis, a scientist at Lawson Health Research Institute, the Robert Hardie Chair of Translational Prostate Cancer Research at the London Regional Cancer Program at London Health Sciences Centre, and Assistant Professor in the Departments of Oncology, Surgery and Medical Biophysics at The Schulich School of Medicine & Dentistry at The University of Western Ontario, is part of a team of scientists that has 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 researchers showed they could stop cancer cells from metastasizing, or spreading from one tumour to establish new tumours elsewhere.

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

According to Dr. Lewis, targeting this protein keeps cancer cells tied to their tumours. 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 tumours of origin. While these results provide only a proof of concept, they suggest it may be possible to design a new way of fighting cancer by treating people with drugs that block CD151.

More than 72,000 Canadians die from cancer each year, making it the leading cause of premature death in this country.

The work started several years ago, when Scripps researcher Dr. James 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, or the ability of cells to crawl. Dr. 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.

Dr. Lewis joined the research team to help identify the precise step in metastasis where the antibody was exerting its effect. Dr. Lewis developed a novel microscope-based imaging system to visualize cancer metastasis in the chick embryo. The group then used this system to capture all of the in vivo imaging data.

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 tumours implanted into them will readily migrate through these blood vessels to form new tumour colonies in under a week. When Dr. Quigley and his colleagues treated the embryos with the antibodies, however, they found that the tumours did not metastasize. Instead, the cancer cells stayed tightly clustered.

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

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 tumours elsewhere.

Dr. Lewis's research team is currently following up on some of the findings by using intravital (live animal) imaging to study the process of intravasation, hopefully leading to news ways of fighting cancer.

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