In 2016, the World Health Organization declared Zika a “Public Health Emergency of International Concern” as the insect-borne virus caused severe damage to the brains of newborn babies. Now, new research suggests its lethal power can be redirected to killing a fatal form of brain cancer known as glioblastoma (GBM) in adult brains. Each year approximately 12,000 people are diagnosed with glioblastoma, which has a median survival rate of only fourteen months post prognosis. Despite aggressive treatments involving surgery, radiation, and chemotherapy, an effective cure that combats the cancer’s malignant cells continues to elude doctors and researchers. As the medical community races towards a cure to fight GBM, which is the most prevalent primary brain tumor, startling new research suggests that the Zika virus, notorious for destroying brain cells in the fetus’ of infected mothers, has the ability to induce cell death in glioblastoma stem cells in adult brains. Zhe Zhu, Matthew J. Gorman, Lisa D. McKenzie and colleagues report on the Zika virus’ efficacy in killing glioblastoma cells that have previously been resistant to cancer drugs, providing hope for those inflicted with the deadly disease.
GBM tumors arise from astrocytes, which are in the family of glial cells. Glial cells are the most abundant cell in the central nervous system as they provide connecting support between neurons and are supported by a large network of blood cells. Moreover, GBM has a cellular hierarchy, with a particularly malignant type of cell known as glioblastoma stem cells (GSC) being the most invasive. Cancerous stem cells mimic normal stem cell behavior; just as stem cells promote growth of new tissues, GSC’s sustain proliferation of cancerous cells, promote tumor growth, and are resistant to treatment. GBM’s acute resistance to treatment is due to GSC’s prodigious capacity to create new cells after tumor removal via surgery or chemotherapy. This capacity has swayed researchers to investigate the effect of viruses with oncolytic activity against GSC’s, because they can be genetically engineered to kill cancer cells without destroying normal tissue.
The Zika virus infects the central nervous system of a developing fetus by targeting and killing neuroprogenitor stem cells, which generate neurons and glial cells during development. These cells are abundant in babies, but decrease in the adult brain, which is why the symptoms of Zika in adults are less severe. This understanding, and the idea that GSCs and neuroprogenitor cells function similarly, prompted the idea that Zika could induce apoptosis (or cell suicide) in GSCs.
To test this hypothesis, researchers first injected patient-derived GSCs with one of two Zika strains, Zika-Brazil or Zika-Dakar, and observed the results of the virus in vitro after 7 days. They found that after 48 hours, 60% of GSCs were infected with the virus and the virus inhibited GSC proliferation. Scientists then expanded the study to test the virus against an in vitro human glioblastoma that included all cell types and found that infection with both Zika-Brazil and Zika-Dakar slowed tumor growth and induced tumor cell death, but did not infect proliferating tumor cells.
After promising results obtained from testing Zika against GBM in laboratory cultures, glioblastoma cells were surgically removed from patients and immediately treated with one of the two strains. Unlike in vitro, the virus was able to infect proliferating cells and induced cell death in GSCs. At this point, however, researchers had yet to test the efficacy of the virus in a living organism. For that reason, researchers generated gliomas in mice and treated them with either a placebo or a mouse-adapted form of the Zika virus. Tumors in mice treated with the virus were significantly smaller than with the placebo and the mice survived longer.
To test the safety of the virus in humans, the scientists injected the virus into normal neural tissue from patients with epilepsy and found that they were not infected and that Zika presents limited toxicity when in the presence of normal brain cells. This result was surprising as other common viruses, such as West Nile Virus, were tested against normal cells and displayed substantial toxicity. Additionally, researchers tested the power of Zika to combat GSCs when combined with a mutation that weakens its ability to combat human cell defenses against infection. While slightly less powerful, the virus was still able to kill malignant cells.
This study is the first step in engineering a form of the Zika virus that in combination with traditional treatment has the potential to eradicate glioblastomas, the most aggressive and deadly form of cancer. The study also demonstrates the importance of rigorously researching pathogens and virus’ lethal behavior to uncover their possible benefits in fighting malignant cells in the human body. The so far promising results will hopefully lead to version of the virus that can extend the lives of those from which it is taken too early.
Zhu, Z., Gorman, et al. (2017). Zika virus has oncolytic activity against glioblastoma stem cells. The Journal of Experimental Medicine. doi:10.1084/jem.2017109309122017c
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