CHARACTERIZATION OF SOMATOSTATIN RECEPTORS ON HUMAN NEUROBLASTOMA TUMORS

Neuroblastoma is the most common extracranial solid tumor of children. Neuroblastoma tumors derive from the neural crest and synthesize neurotransmitters including the neuropeptide somatostatin. This study was designed to characterize somatostatin receptors both in primary neuroblastoma tumors and in two neuroblastoma cell lines, SKNSH and IMR32. Somatostatin receptors were identified in 6 of 7 Stage I and II compared to 7 of 19 Stage III and IV tumors. Down-regulation of somatostatin receptor binding was observed in five tumors during disease progression. A lack of high affinity binding of somatostatin was identified as a poor prognostic indicator; negative binding correlated with advanced disease and death. Somatostatin receptor binding was observed in the IMR32 cell line, but not in the SKNSH cell line. IMR32 cells demonstrated a single class of high affinity binding sites for both somatostatin and a synthetic analogue, octreotide (K(d) 0.16 +/- 0.05 nm and 0.89 +/- 0.23 nm, respectively). Somatostatin and octreotide inhibited both vasoactive intestinal peptide-mediated and forskolin-mediated cyclic AMP accumulation in IMR32 cells. Somatostatin and octreotide inhibition of signal transduction was attenuated by pretreatment of the cells with pertussis toxin. Octreotide inhibited proliferation of IMR32 cells by 70% in a 6-day culture. In contrast, octreotide did not exhibit high affinity binding in SKNSH cells and had no effect on cyclic AMP accumulation or on proliferation in SKNSH cells. Together, these data indicate that octreotide interacts with high affinity somatostatin receptors to modulate signal transduction and regulate proliferation in neuroblastoma cell lines. These data also suggest that somatostatin receptor expression may be an independent prognostic factor in primary neuroblastoma tumors.