Neuroblastoma cell lines contain pluripotent tumor initiating cells that are susceptible to a targeted oncolytic virus.
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.


RESULTS
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
These results suggest that human neuroblastoma contains tumor initiating cells that may be effectively targeted by an oncolytic virus.
Mahller
Yonatan Y
YY
Division of Hematology and Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
Williams
Jon P
JP
Baird
William H
WH
Mitton
Bryan
B
Grossheim
Jonathan
J
Saeki
Yoshinaga
Y
Cancelas
Jose A
JA
Ratner
Nancy
N
Cripe
Timothy P
TP
D000071916:AC133 Antigen; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D045744:Cell Line, Tumor; D019070:Cell Lineage; D002522:Chlorocebus aethiops; D015972:Gene Expression Regulation, Neoplastic; D006023:Glycoproteins / Q000096:biosynthesis; D006801:Humans; D007381:Intermediate Filament Proteins / Q000096:biosynthesis; D009363:Neoplasm Proteins / Q000096:biosynthesis; D014411:Neoplastic Stem Cells / Q000166:cytology*; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D064231:Nestin; D009447:Neuroblastoma / Q000378:metabolism*; D050504:Oncolytic Viruses / Q000378:metabolism*; D010455:Peptides; D013234:Stem Cells / Q000378:metabolism; D014158:Transcription, Genetic; D014709:Vero Cells
C116614:ABCG2 protein, human; D000071916:AC133 Antigen; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D015703:Antigens, CD; D006023:Glycoproteins; D007381:Intermediate Filament Proteins; C577484:NES protein, human; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse