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Stem cells track tumors
By Bijal P. Trivedi

Researchers have shown that neural stem cells—which can develop into any type of brain cell—sense and migrate toward brain tumors. This migratory ability could make stem cells the ideal courier for delivering toxic compounds to the doorstep of the tumor cell. In a preliminary study in mice, researchers found that they could shrink tumors by 80 percent using this approach.

Neural stem cells (red) infiltrate and surround the tumor (green).

The finding holds particularly interesting possibilities for malignant brain cancers whose cells aggressively spread throughout normal brain tissue seeding new tumors, a characteristic that makes treatment almost impossible. The authors of the new study suggest that specially prepared stem cells injected in or near the tumor would track and destroy tumor cells that have metastasized and left the main growth.

An abstract of the work was presented at the third annual meeting of the American Society of Gene Therapy in June, and now the full article appears in the current issue of the Proceedings of the National Academy of Sciences.

To test the migratory potential of the stem cells, researchers created a population of mice with tumors in the right frontal lobe of the brain. They injected the stem cells in different locations in the brain and body to see whether the cells were able to find the tumor. Mice received the injections directly into the brain tumor, close to the tumor, in the left side of the brain, or in the tail vein.

The researchers can follow the activities of the tumor cells and the stem cells because each is labeled with a different color dye: tumor cells are a fluorescent green, whereas stem cells are red. The stem cells injected directly into the tumor infiltrate the entire growth and migrate just outside the border of the tumor to surround or encapsulate it. "The tumor ends up looking a bit like a Christmas tree covered in red lights," says Evan Snyder, of Harvard's Children's Hospital in Boston, who led the study.

Tumor cells that begin to stray from the main tumor are followed by a string of stem cells that seem to be tracking and surrounding these escapees, says Snyder.

Stem cells injected close to the tumor migrated through normal healthy adult brain tissue to infiltrate the tumor. The ones that were implanted on the other side of the brain migrated through one side of the brain, across the corpus callosum, the region that divides the brain, and directly to the tumor. Even the cells injected in the tail vein found their way to the tumor in the brain.

These first experiments used mouse stem cells and rat tumor implants. The team found that when these experiments were repeated using human neural stem cells, the stem cells migrated toward human brain tumor implants in the mouse brain just like their mouse counterparts.

To explore the therapeutic potential of stem cells, Snyder's team engineered cells that carry a gene for the production of cytosine deaminase (CD). CD converts a benign, non-toxic drug called 5-fluorocytosine into a toxic compound that kills rapidly dividing tumor cells. After two weeks, tumors that were treated with the therapeutic stem cells had shrunk by 80 percent.

Snyder's work is an "important new contribution" that "brings us closer to the point where clinical trials will be initiated on the use of neural stem cells to treat CNS tumors," says Mark Noble, of the University of Rochester Medical Center, in a commentary accompanying the article in PNAS.

However, Noble points out that Snyder's work has yet to prove that the tumor cell and neural stem cells are not traveling along previously defined travel routes that force the same migration patterns. He also suggests that further work is needed to prove that stem cells can hunt down an individual tumor cell that infiltrates healthy tissue. There are also questions as to whether these therapeutic cells cause brain damage by migrating through the brain.

The next two years will be spent developing therapeutic human neural stem cells for use in clinical trials. Snyder is also planning to spend time on the basic science; finding the signals that direct neural stem cell migration.

The ideal stem cell would first kill the tumor cell and then differentiate into normal brain cells repairing tumor damage and reestablishing the neural architecture. "That would be the home run," says Snyder.

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Noble, M. Can neural stem cells be used to track down and destroy migratory brain tumor cells while also providing a means of repairing tumor-associated damage? Proc Natl Acad Sci USA 97, 12393-12395 (November 7, 2000).
Aboody, K.S. et al. Neural stem cells display extensive tropism for pathology in adult brain: Evidence from intracranial gliomas. Proc Natl Acad Sci USA 97, 12486-12851 (November 7, 2000).

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