Clonal human neuroblastoma cells SH-IN undergo a very conspicuous phenotypic change in culture. Large substrate-adherent cells with a slow growth rate give rise to small cells emerging in focal aggregates and growing to high cell densities. This is accompanied by a dramatic switch in the expression of receptors for the structurally related neuropeptides VIP (vasoactive intestinal polypeptide) and PACAP (pituitary adenylate cyclase activating polypeptide). Large cells expressed mainly PACAP-specific receptors that triggered stimulation of intracellular cGMP production. On the other hand, polyvalent VIP/PACAP receptors positively coupled to adenylate cyclase were mostly observed in the small cells. Both neuropeptides stimulated cell proliferation in large and small cells. These data, together with the previous demonstration of autocrine/paracrine actions of VIP and PACAP in human neuroblastomas, support the idea that these neuropeptides may participate in the establishment of the apparent phenotype in these cancer cells.
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