Researchers reporting in PLoS One also engineered a herpes virus to kill progenitor cells in mice.

Pediatric neuroblastomas seem to have a population of cells with stem-cell characteristics, according to researchers at the Cincinnati Children’s Hospital Medical Center. They also report being able to reprogram an oncolytic herpes simplex virus to eliminate these progenitor cells in mice.

Since neural stem cells and neuroblastoma cells both carry the protein nestin, investigators tested the effect of virus rQNestin34.5 on cells. This genetically programmed virus carries a molecular promoter for nestin, which causes it to seek out the protein and cancerous or precancerous cells where nestin resides. The virus was designed to grow inside and be toxic to cancer cells but not healthy tissue.

Although a promising step forward, Timothy Cripe, M.D., Ph.D., senior investigator of the study, noted that precancerous cells were infected with the oncolytic virus in a laboratory culture before being injected into mice. “Targeting and hitting the cells after they are already in the mice will be another matter.” 

The scientists grew human neuroblastoma cells in laboratory cultures. They found that the cultures contained cells exhibiting biological properties of neural stem cells. The cultures generated cell colonies that acted like stem cells in how they divided and grew. Out of eight cell lines, three could be induced into multi-lineage differentiation. Analysis showed that all cells carried known biological markers for nerve stem cells, such as the proteins CD133, ABCG2, and nestin.

Additionally, four formed tumorspheres in neural stem cell media. Cells derived from these tumorspheres were relatively resistant to doxorubicin. Researchers also noted that cells from the tumorspheres carried a gene called MYCN, which is found at amplified levels in aggressive forms of neuroblastoma.

The tumorigenic cells were infected with rQNestin34.5 and then injected into mice. Tumors did not form in any of the mice over a 60-day observation period, leading the researchers to report that rQNestin34.5 abolished tumor growth by attacking apparent tumor-initiating cells.

The scientists also infected tumorigenic cells with another oncolytic herpes virus called rQLuc, which does not target cells that contain the nestin protein. rQLuc showed only moderate success, with all treated mice having tumor formation within 40 days. In mice where cells were treated only with saline, all animals had tumors within 30 days.

The results are published online January 21 in PLoS One.


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