The combination of gamma-interferon and tumor necrosis factor causes a rapid and extensive differentiation of human neuroblastoma cells.
Neuroblastoma (NB), a tumor originating from the sympathetic nervous system, is the most common extracranial neurological tumor of childhood. Human NB cells may differentiate in vitro under treatment with biological agents, as gamma-interferon (IFN-gamma) and tumor necrosis factor (TNF). Unfortunately, NB cell lines resistant to the differentiation-inducing effects of both drugs have been observed. Here we demonstrate that a combination of IFN-gamma plus TNF causes extensive and generalized differentiation of NB cells toward a neuronal phenotype. Both IFN-gamma and TNF, given alone, moderately reduced cell growth and induced partial morphological maturation. Their combination further reduced cell proliferation. The combined treatment gave a synergistic rather than additive cytostatic effect, documented also by a dramatically enhanced differentiation toward a neuronal morphology. Membrane immunofluorescence showed a homologous and heterologous up-regulation of IFN-gamma receptor, as well as a marked induction of HLA Class I antigens and, to a lesser extent, of Class II antigens on NB cells induced to differentiate. Treatment of NB cell lines with IFN-gamma/TNF results in the induction of a differentiated phenotype, as indicated by the increased expression of the Mr 160,000 and 200,000 neurofilament proteins and that of microtubule-associated proteins. Evaluation of biochemical markers of neuronal differentiation confirmed the ability of the combined treatment to induce neuroblast maturation. These results suggest that the combination of IFN-gamma and TNF should be considered for experimental clinical trials in neuroblastoma.
Pediatric Oncology Research Laboratory, G. Gaslini Children's Hospital, Genoa, Italy.
M
M
Ponzoni
A
A
Casalaro
M
M
Lanciotti
P G
PG
Montaldo
P
P
Cornaglia-Ferraris
D000110:Acetylcholinesterase / Q000378:metabolism; D000954:Antigens, Surface / Q000032:analysis; D002454:Cell Differentiation / Q000187:drug effects*; D003598:Cytoskeletal Proteins / Q000032:analysis / Q000378:metabolism; D004261:DNA Replication / Q000187:drug effects; D004295:Dihydroxyphenylalanine / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D004357:Drug Synergism; D005455:Fluorescent Antibody Technique; D006801:Humans; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology*; D007700:Kinetics; D009447:Neuroblastoma / Q000378:metabolism / Q000473:pathology*; D009638:Norepinephrine / Q000378:metabolism; D010751:Phosphopyruvate Hydratase / Q000032:analysis; D011994:Recombinant Proteins / Q000494:pharmacology; D012701:Serotonin / Q000378:metabolism; D013936:Thymidine / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D000954:Antigens, Surface; D003598:Cytoskeletal Proteins; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D004295:Dihydroxyphenylalanine; D007371:Interferon-gamma; D000110:Acetylcholinesterase; D010751:Phosphopyruvate Hydratase; D013936:Thymidine; D004298:Dopamine; D009638:Norepinephrine