Presence of nerve growth factor-like immunoreactivity in carcinoid tumour cells and induction of a neuronal phenotype in long-term culture

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Abstract
Mid‐gut carcinoid tumour cells expressed a neuronal phenotype, observed and characterized immunocytochemically in long‐term culture. Initially the culture contained a main population of spherical tumour cells with granules immuno‐positive for serotonin (5‐HT) and tachykinins (TK). Production and secretion of these substances into media was verified biochemically. Cytoplasmic granules with 5‐HT‐like immuno‐reactivity (5‐HT‐LI) were markedly reduced during culture, while granules with TK‐LI were unchanged in number, corresponding to the biochemical findings. After a few days in culture, tumour cells were flattened and fine neurite‐like processes extended. After 2‐3 weeks many endocrine tumour cells had converted to neuron‐like cells with slender cell processes containing granules with TK‐LI. Varicose enlargements and apparent growth cones were observed. When neurites were extended, 50‐80% of the neuron‐like cells were positive with antisera against the neurofilament triplet. Cells of both endocrine and neuronal phenotypes were positive with antisera against tetanustoxin, Thy I‐antigen, neuron‐specific enolase, synapsin and a synaptic vesicle protein (p 38) supporting the concept of these tumour cells as para‐neurons. Intermediate filaments, studied with monoclonal anti‐vimentin, were found in all cells. Filaments were also observed ultrastructurally. Initially, nerve growth factor (NGF)‐LI was found in granules of all spherical tumour cells. When neuritic processes were extended, the cells appeared to lose these granules. After 40 days in culture, NGF‐LI was absent or very sparse. The studies indicate autocrine secretion of a growth factor, reacting with the NGF antiserum, by cultured midgut carcinoid tumour cells inducing a neuronal phenotype with enhanced NF and TK synthesis and suppressed 5‐HT synthesis. In bioassay systems the culture media caused a delayed neurite reaction on PC12 cells, but no reaction on chick ciliary ganglion cells, indicating that the factor is not authentic NGF.