Bladder Ca: New findings on its course, metastasis

Two recent studies appear to shed light on the effect of smoking on bladder cancer outcomes and the role a certain protein plays in metastatic disease.

In the first study, smoking was found to not only cause bladder cancer but also affect its course, in that people who smoke more have greater likelihood of developing more aggressive and deadly disease.

The study, which was published online in Cancer (Jan. 14, 2013), also found that a panel of bladder cancer markers can predict which particular cases are at the highest risk for a fatal outcome.

Senior author Richard J. Cote, MD, of University of Southern California Keck School of Medicine, Los Angeles, led a team that analyzed bladder tumors and smoking history in 212 multi-ethnic patients recruited through the Los Angeles County Cancer Surveillance Program between 1987 and 1996.

The authors found that the bladder cancers that developed in individuals who smoked intensely were more likely to be deadly than bladder cancers that developed in those who never smoked or who smoked less. The study also revealed that changes in particular proteins are often present in bladder cancers that have become deadly. Patients with alterations in six to nine markers had a very poor outcome, raising the hypothesis that these individuals could have benefited from more aggressive treatments.

"The study’s findings are extremely clinically relevant, as bladder cancer is one of the most expensive malignancies to treat," Dr. Cote said. "Personalized patient management is urgently needed for this disease, as current clinical stratification cannot predict outcomes of individual patients."

Because the number of changes in these proteins was directly proportional to patients’ health outcomes in a progressive fashion, the findings confirm the theory that an accumulation of changes is more important than individual changes in determining the characteristics of a given cancer. The link between smoking intensity and prognosis found in this study points to the incrementally harmful effects of smoking.

A second study from the University of Colorado Cancer Center, Aurora, published online in the Journal of Clinical Investigation (Jan. 16, 2013), shows that the protein SPARC (Secreted Protein Acidic and Rich in Cysteine) acts much like an anti-inflammatory drug, attempting to heal tissues inflamed by tumors. Likewise, cancers-for example, bladder cancer in this study-have developed ways to turn off the production of SPARC, thus allowing growth and metastasis, especially to the lung.

"In fact, we show the effects of SPARC go beyond even this anti-inflammatory role. Additionally, the protein is involved in disallowing migrating cancer cells from attaching at possible metastasis sites and stopping the production of new blood vessels needed to feed tumor tissue," said lead author Dan Theodorescu, MD, PhD.

The study started by evaluating SPARC levels in human bladder cancer samples. In less aggressive cancers, both the tumor and the surrounding tissue made SPARC. In more aggressive cancers, it was just the surrounding tissue that made SPARC-the aggressive tumor itself had suppressed production of the protein. In these human bladder cancer tumors, more SPARC was associated with longer survival.

Then Dr. Theodorescu and colleagues turned to animal models without the ability to manufacture SPARC. Not only was bladder cancer quicker to develop in these models, but the cancer was also more likely to travel to invade lung tissue. When SPARC was added to these models, tumor growth and metastasis was reduced.

"This is a comprehensive portrait of SPARC function using human and murine bladder cancer as a model, and the first to clearly distinguish between the role of SPARC generated in the tumor and the role of the protein generated in the surrounding tissue," said Dr. Theodorescu. "We hope this provides the rational basis for further exploring manipulation of SPARC as a therapeutic intervention."

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