Protein fights protein to keep bladder cancer away from the lungs

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Researchers have found what they believe to be a new mechanism of metastasis suppression that prevents bladder cancer from spreading to the lungs.

Half of patients with muscle-invasive bladder cancer develop metastatic disease. This, in turn, is responsible for most deaths caused by bladder cancer, noted researchers Dan Theodorescu, MD, PhD, director of the University of Colorado Cancer Center in Aurora, Colorado, and colleagues, in their report for The Journal of Clinical Investigation. The team demonstrated that a protein involved in cancer cell migration is a driver of lung metastasis. High levels of the protein, versican, are associated with poor prognosis in persons with bladder cancer.

When cancer cells metastasize and have trouble surviving at the distant site, they express their distress in the form of versican. Macrophages respond to the distress signal, helping the cells to thrive and metastasis to occur. Theodorescu's team showed that when a cancer cell makes another protein, RhoGDI2, the cell's production of versican is reduced. In vitro and in vivo (mouse models), RhoGDI2 suppressed lung metastasis by reducing the expression of versican. Further analysis indicated that RhoGDI2 suppressed metastasis by altering inflammation in the tumor microenvironment.

In another significant discovery involving a third protein, this one known as CCL2, the investigators learned that versican's ability to attract macrophages relies on CCL2. Drugs that inhibit CCL2 are already being evaluated in clinical trials for other conditions.

“For a decade, we've known that the major challenge of treating bladder cancer is treating or preventing the metastatic form of the disease,” affirmed Theodorescu in a statement announcing his group's findings. “This study represents an advance in the latter—by preventing the spread of bladder cancer to the lungs, we could improve patient survival.”


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