Researchers hijack cancer migration mechanism to ‘move’ brain tumors

February 25, 2014

A researcher retrieves samples of glioblastoma cells for study in the laboratory of Ravi Bellamkonda at Georgia Tech and Emory University (credit: Georgia Tech Photo, Rob Felt)

One factor that makes glioblastoma cancers so difficult to treat is that malignant cells from the tumors spread throughout the brain by following nerve fibers and blood vessels to invade new locations.

Now, Georgia Tech and Emory University researchers have learned to hijack this migratory mechanism, turning it against the cancer by using a film of nanofibers to lure tumor cells away.

Instead of invading new areas, the migrating cells latch onto the specially-designed nanofibers and follow them to a location — potentially outside the brain — where they can be captured and killed.

Moving tumors to accessible locations

Using this technique, researchers can partially move tumors from inoperable locations to more accessible ones. Though it won’t eliminate the cancer, the new technique reduced the size of brain tumors in animal models, suggesting that this form of brain cancer might one day be treated more like a chronic disease.

“We have designed a polymer thin film nanofiber that mimics the structure of nerves and blood vessels that brain tumor cells normally use to invade other parts of the brain,” explained Ravi Bellamkonda, lead investigator and chair of the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University. “The cancer cells normally latch onto these natural structures and ride them like a monorail to other parts of the brain. By providing an attractive alternative fiber, we can efficiently move the tumors along a different path to a destination that we choose.”

Tumor cells typically invade healthy tissue by secreting enzymes that allow the invasion to take place, she explained. That activity requires a significant amount of energy from the cancer cells. “Our idea was to give the tumor cells a path of least resistance, one that resembles the natural structures in the brain, but is attractive because it does not require the cancer cells to expend any more energy,” she explained.

Nanofibers serve as tumor guides

Experimentally, the researchers created fibers made from polycaprolactone (PCL) polymer surrounded by a polyurethane carrier. The fibers, whose surface simulates the contours of nerves and blood vessels that the cancer cells normally follow, were implanted into the brains of rats in which a human GBM tumor was growing. The fibers served as tumor guides, leading the migrating cells to a “tumor collector” gel containing the drug cyclopamine, which is toxic to cancer cells. For comparison, the researchers also implanted fibers containing no PCL or an untextured PCL film in other rat brains, and left some rats untreated. The tumor collector gel was located physically outside the brain.

After 18 days, the researchers found that compared to other rats, tumor sizes were substantially reduced in animals that had received the PCL nanofiber implants near the tumors. Tumor cells had moved the entire length of all fibers into the collector gel outside the brain.

Treating brain cancer with nanofibers could be preferable to existing drug and radiation techniques, Bellamkonda said.

Before the technique can be used in humans, however, it will have to undergo extensive testing and be approved by the FDA — a process that can take as much as ten years. Among the next steps are to evaluate the technique with other forms of brain cancer, and other types of cancer that can be difficult to remove.

The research was supported by the National Cancer Institute (NCI), part of the National Institutes of Health; by Atlanta-based Ian’s Friends Foundation, and by the Georgia Research Alliance. In addition to the Coulter Department of Biomedical Engineering, the research team included Children’s Healthcare of Atlanta and Emory University.

Abstract of Nature Materials paper

Glioblastoma multiforme is an aggressive, invasive brain tumour with a poor survival rate. Available treatments are ineffective and some tumours remain inoperable because of their size or location. The tumours are known to invade and migrate along white matter tracts and blood vessels. Here, we exploit this characteristic of glioblastoma multiforme by engineering aligned polycaprolactone (PCL)-based nanofibres for tumour cells to invade and, hence, guide cells away from the primary tumour site to an extracortical location. This extracortial sink is a cyclopamine drug-conjugated, collagen-based hydrogel. When aligned PCL-nanofibre films in a PCL/polyurethane carrier conduit were inserted in the vicinity of an intracortical human U87MG glioblastoma xenograft, a significant number of human glioblastoma cells migrated along the aligned nanofibre films and underwent apoptosis in the extracortical hydrogel. Tumour volume in the brain was significantly lower following insertion of aligned nanofibre implants compared with the application of smooth fibres or no implants.