Study appearing in PNAS also suggests how these cells evade the immune system.

Researchers at Stanford’s School of Medicine have reportedly identified the first human bladder cancer stem cell and describe how it works to escape the body’s natural defenses. In particular they pinpointed a gene that encodes a cell-surface molecule called CD47 as key to how bladder cancer stem cells avoid the immune system.

The results are published online August 3 in the Proceedings of the National Academy of Sciences. The study evaluated two main types of bladder cancer: one that invades the muscle around the bladder and metastasizes to other organs and another that remains confined to the bladder lining.

The researchers used breast cancer stem cell markers to identify a subpopulation of human bladder cancer cells with stem cell qualities; i.e., the cells formed tumors when transplanted into mice with compromised immune systems. They then assessed which genes were more highly expressed in these cells than in other bladder cancer cells from the same tumor.

Most but not all noninvasive bladder cancers expressed lower levels of these genes than did invasive cancers. Further research showed that the anomalous noninvasive cancers with higher levels of gene expression behaved more aggressively: About 80% recurred within 25 months of initial diagnosis, whereas only about 20% of the low-expressing tumors did so.

“The fact that we were able to pull out the subpopulation of these cancers that will become invasive is an important step in identifying those that will be more dangerous,” points out post-doctoral fellow Keith Syson Chan, Ph.D., who was the first author of the paper. “It may be possible to follow the progress of the tumor by analyzing the expression levels of these genes.”

Dr. Chan and his team found one gene particularly interesting. This gene encodes a cell-surface molecule called CD47. They knew from their previous research that CD47 prevents leukemia cells from being engulfed by macrophages by binding to a molecule on the surface of the macrophage. Blocking this interaction with an antibody specific for CD47 allowed the macrophages to swallow the leukemia cells. When they tried a similar experiment with the bladder cancer stem cells in a test tube, the same thing happened.

“Leukemia is totally different from the kind of epithelial cancer we see in the bladder,” notes Dr. Chan, “so it was very exciting to see that these two kinds of cancer stem cells use a similar mechanism to escape the macrophages. It’s also very interesting to find that macrophages seem to be playing such a major role in cancer progression.”

The researchers are now investigating whether CD47 is expressed at high levels on other cancer stem cells. They’re also trying to find ways to help circulating macrophages better infiltrate solid tumors.

“This is first time we’ve found this ‘don’t eat me’ signal in a stem cell of a solid cancer,” remarks Irving Weissman, M.D., the Virginia & D.K. Ludwig professor for clinical investigation in cancer research at the medical school. “We’re now moving as fast as we can to look at other tumors to see if this is a universal strategy of all or most cancer stem cells.”

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