Low-dose interferon-gamma-producing human neuroblastoma cells show reduced proliferation and delayed tumorigenicity.
Interferon-gamma (IFN-gamma) directs T helper-1 cell differentiation and mediates antitumour effects in preclinical models. However, high-dose IFN-gamma is toxic in vivo, and IFN-gamma-transfected neuroblastoma (NB) cells secreting high amounts of the cytokine may be lost due to cell apoptosis or differentiation. Two human NB cell lines (ACN and SK-N-BE2(c)) differing as to genetic and phenotypic features were transfected with the human IFN-gamma gene and selected on the grounds of the low concentrations of IFN-gamma produced. In both IFN-gamma-transfected cell lines, autocrine and paracrine activation of IFN-gamma-mediated pathways occurred, leading to markedly reduced proliferation rate, to increased expression of surface HLA and CD40 molecules and of functional TNF binding sites. ACN/IFN-gamma cells showed a significantly delayed tumorigenicity in nude mice as compared to parental cells. ACN/IFN-gamma tumours were smaller, with extensive necrotic area as a result of a damaged and defective microvascular network. In addition, a significant reduction in the proliferation index was observed. This is the first demonstration that IFN-gamma inhibits in vivo proliferation of NB cell by acting on the tumour cell itself. This effect adds to the immunoregulatory and antiangiogenic activities operated by IFN-gamma in syngeneic tumour-bearing hosts.
Airoldi
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I
Laboratory of Oncology, Gaslini Institute, Largo Gaslini 5, 16148 Genoa, Italy.
Meazza
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R
Croce
M
M
Di Carlo
E
E
Piazza
T
T
Cocco
C
C
D'Antuono
T
T
Pistoia
V
V
Ferrini
S
S
Corrias
M V
MV
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects*; D017931:DNA Primers; D005260:Female; D005434:Flow Cytometry; D015316:Genetic Therapy; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental; D009389:Neovascularization, Pathologic; D009447:Neuroblastoma / Q000276:immunology* / Q000473:pathology*; D010641:Phenotype; D018124:Receptors, Tumor Necrosis Factor / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D017931:DNA Primers; D018124:Receptors, Tumor Necrosis Factor; D007371:Interferon-gamma