BACKGROUND: Although disease remission can frequently be achieved for patients with neuroblastoma, relapse is common. The cancer stem cell theory suggests that rare tumorigenic cells, resistant to conventional therapy, are responsible for relapse. If true for neuroblastoma, improved cure rates may only be achieved via identification and therapeutic targeting of the neuroblastoma tumor initiating cell. Based on cues from normal stem cells, evidence for tumor populating progenitor cells has been found in a variety of cancers. METHODOLOGY/PRINCIPAL FINDINGS: Four of eight human neuroblastoma cell lines formed tumorspheres in neural stem cell media, and all contained some cells that expressed neurogenic stem cell markers including CD133, ABCG2, and nestin. Three lines tested could be induced into multi-lineage differentiation. LA-N-5 spheres were further studied and showed a verapamil-sensitive side population, relative resistance to doxorubicin, and CD133+ cells showed increased sphere formation and tumorigenicity. Oncolytic viruses, engineered to be clinically safe by genetic mutation, are emerging as next generation anticancer therapeutics. Because oncolytic viruses circumvent typical drug-resistance mechanisms, they may represent an effective therapy for chemotherapy-resistant tumor initiating cells. A Nestin-targeted oncolytic herpes simplex virus efficiently replicated within and killed neuroblastoma tumor initiating cells preventing their ability to form tumors in athymic nude mice. CONCLUSIONS/SIGNIFICANCE: These results suggest that human neuroblastoma contains tumor initiating cells that may be effectively targeted by an oncolytic virus.Examples of news items about this publication:
Targeting Cancer's Own Stem Cells to Fight Recurrence, Forbes, January 21, 2009. First paragraph:
Scientists have located a group of cancer stem cells or "tumor-initiating cells" which, when targeted with a reprogrammed herpes virus, are prevented from turning malignant.Engineered Virus Targets And Kills Apparent Cancer Stem Cells In Neuroblastoma, ScienceDaily, January 21, 2009. First paragraph:
After identifying an apparent population of cancer stem cells for neuroblastoma, researchers successfully used a reprogrammed herpes virus to block tumor formation in mice by targeting and killing the cells.Virus made to kill cancer stem cells, UPI, January 22, 2009. First paragraph:
U.S. scientists say they have engineered a virus to target and kill apparent cancer stem cells involved in neuroblastoma tumors.