Oncolytic Virus Specifically Kills Neuroblastoma Tumors in Mouse Model

The cancer cells produced tumorspheres that were relatively resistant to the chemotherapy agent doxorubicin and carried known biological markers for nerve stem cells, such as the proteins CD133 and nestin. The latter observation indicated that some of the tumor cells represented a type of cancer stem cell that was possibly responsible for initiation of tumor growth.

Nestin is a type VI intermediate filament protein expressed in dividing cells during the early stages of development in the central nervous system (CNS), the peripheral nervous system (PNS), and in myogenic and other tissues. Upon differentiation, nestin becomes downregulated and it is replaced by tissue-specific intermediate filament proteins. Nestin expression is reinduced in the adult during pathological situations, such as the formation of the glial scar after CNS injury and during regeneration of injured muscle tissue. Nestin expression has been extensively used as a marker for CNS progenitor cells in different contexts, based on observations indicating a correlation between nestin expression and this cell type in vivo.

Since neural stem cells and neuroblastoma cells both carry nestin, the investigators examined the effect of an oncolytic herpes simplex virus called rQNestin34.5 on the neuroblastoma tumorsphere cells. This virus had been genetically engineered specifically to invade and destroy cells containing nestin, but to be otherwise harmless.

The investigators reported in the January 21, 2009, online edition of the journal PLoS (Public Library of Science) One, that they infected neuroblastoma tumorsphere cells with rQNestin34.5 and then injected them into a group of mice. A control group was injected with similar tumorsphere cells that had been infected with a different oncolytic herpes virus called rQLuc, which did not target nestin-containing cells.

Tumors did not form in any of the mice that had received the rQNestin34.5 treated cells over a 60-day observation period. The mice that had received the rQLuc treated cells developed tumors within 40 days, while mice where the cells were treated only with saline had tumors form within 30 days.

"The main finding of our study is that pediatric neuroblastomas seem to have a population of cells with stem-cell characteristics that we may need to target for therapy," said senior author Dr. Timothy Cripe, professor of pediatrics at Cincinnati Children's Hospital Medical Center. "We also show that one promising approach for targeted treatment is biological therapy, such as an engineered oncolytic virus that seeks out and kills progenitor cells that could be the seeds of cancers."

Dr. Cripe cautioned about the potential use of oncolytic viruses in therapy when he pointed out that, "The study's main limitation was 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."

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Cincinnati Children's Hospital Medical Center