Zika Virus Kills Glioblastoma Stem Cells, New Research Shows | Medicine

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In a research paper published this week in the Journal of Experimental Medicine, scientists report that Zika virus could be used to target and kill brain cancer stem cells, the kind of cells most resistant to standard treatments.

Space-fill drawing of the outside of one Zika virus particle, and a cross-section through another as it interacts with a cell. The two main proteins of the viral envelope, the envelope proteins and membrane proteins, are shown in red and purple respectively. The lipid membrane of the envelope is shown in light lavender.The capsid proteins, in orange, are shown interacting with the RNA genome, in yellow, at the center of the virus. The cell-surface receptor proteins are in green, the cytoskeleton in blue, and blood plasma proteins in gold. Image credit: David Goodsell.

Space-fill drawing of the outside of one Zika virus particle, and a cross-section through another as it interacts with a cell. The two main proteins of the viral envelope, the envelope proteins and membrane proteins, are shown in red and purple respectively. The lipid membrane of the envelope is shown in light lavender.The capsid proteins, in orange, are shown interacting with the RNA genome, in yellow, at the center of the virus. The cell-surface receptor proteins are in green, the cytoskeleton in blue, and blood plasma proteins in gold. Image credit: David Goodsell.

“We showed that Zika virus can kill the kind of glioblastoma cells that tend to be resistant to current treatments and lead to death,” said Michael S. Diamond, the Herbert S. Gasser Professor of Medicine at Washington University School of Medicine.

Each year in the United States, about 12,000 people are diagnosed with glioblastoma, the most common form of brain cancer. Among them is U.S. Sen. John McCain, who announced his diagnosis in July.

Just like normal, healthy tissues, the growth and development of glioblastomas is driven by stem cells that proliferate and give rise to other tumor cells.

Glioblastoma stem cells are hard to kill because they can avoid the body’s immune system and are resistant to chemotherapy and radiation. But killing these cells is vital to prevent new tumors from recurring after the original tumor has been surgically removed.

In their neurological origins and near-limitless ability to create new cells, glioblastoma stem cells reminded Professor Diamond and co-authors of neuroprogenitor cells, which generate cells for the growing brain. Zika virus specifically targets and kills neuroprogenitor cells.

The researchers tested whether the virus could kill stem cells in glioblastomas removed from patients at diagnosis.

They infected tumors with one of two strains of Zika virus. Both strains spread through the tumors, infecting and killing the cancer stem cells while largely avoiding other tumor cells.

The findings suggest that Zika infection and chemotherapy-radiation treatment have complementary effects.

The standard treatment kills the bulk of the tumor cells but often leaves the stem cells intact to regenerate the tumor. Zika virus attacks the stem cells but bypasses the greater part of the tumor.

“We see Zika one day being used in combination with current therapies to eradicate the whole tumor,” said co-author Dr. Milan G. Chheda, also from Washington University School of Medicine.

To find out whether the virus could help treat cancer in a living animal, the team injected either Zika virus or saltwater (placebo) directly into the brain tumors of 18 and 15 mice, respectively. Tumors were significantly smaller in the Zika-treated mice two weeks after injection, and those mice survived significantly longer than the ones given saltwater.

If Zika were used in people, it would have to be injected into the brain, most likely during surgery to remove the primary tumor. If introduced through another part of the body, the person’s immune system would sweep it away before it could reach the brain.

The idea of injecting a virus notorious for causing brain damage into people’s brains seems alarming, but Zika may be safer for use in adults because its primary targets — neuroprogenitor cells — are rare in the adult brain.

The fetal brain, on the other hand, is loaded with such cells, which is part of the reason why Zika infection before birth produces widespread and severe brain damage, while natural infection in adulthood causes mild symptoms.

“Adults with Zika may suffer less damage from their infection, suggesting that this approach could be used with acceptable toxicity,” said co-author Dr. Jeremy Rich, from the University of California, San Diego, and the Cleveland Clinic Lerner Research Institute.

Brain cancer stem cells (left) are killed by Zika virus infection (image at right shows cells after Zika treatment). Image credit: Zhe Zhu.

Brain cancer stem cells (left) are killed by Zika virus infection (image at right shows cells after Zika treatment). Image credit: Zhe Zhu.

The scientists conducted additional studies of the virus using brain tissue from epilepsy patients and showed that the virus does not infect noncancerous brain cells.

As an additional safety feature, they introduced two mutations that weakened the virus’ ability to combat the cell’s defenses against infection, reasoning that the mutated virus still would be able to grow in tumor cells — which have a poor antiviral defense system — but would be eliminated quickly in healthy cells with a robust antiviral response.

When they tested the mutant viral strain and the original parental strain in glioblastoma stem cells, they found that the original strain was more potent, but that the mutant strain also succeeded in killing the cancerous cells.

“Our study is a first step towards the development of safe and effective strains of Zika virus that could become important tools in neuro-oncology and the treatment of glioblastoma,” Professor Diamond said.

“However, public health concerns will need to be addressed through pre-clinical testing and evaluations of the strains’ ability to disseminate or revert to more virulent forms.”

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Zhe Zhu et al. Zika virus has oncolytic activity against glioblastoma stem cells. Journal of Experimental Medicine, published online September 5, 2017; doi: 10.1084/jem.20171093