Vasoactive intestinal peptide (VIP) stimulates in vitro growth of VIP-1 receptor-bearing human pancreatic adenocarcinoma-derived cells

Abstract

Vasoactive intestinal peptide (VIP) appears to be responsible for atropine-resistant, neurally mediated pancreatic ductal bicarbonate secretion and plays a role in both stimulation and inhibition of neoplastic growth in other organs. cDNAs encoding high affinity VIP-1 and VIP-2 receptors have been cloned, and these receptors may be differentiated based on the ability of VIP-1, but not VIP-2, receptors to couple to adenylyl cyclase in response to stimulation with micromolar concentrations of secretin. Recent data from our laboratory suggest expression of a low affinity secretin receptor in seven cell lines derived from human ductal pancreatic adenocarcinomas. In combination with the recent use of (123)I-labeled VIP to successfully image pancreatic adenocarcinomas in humans and the high affinity binding of both VIP and pituitary adenylate cyclase-activating peptides to sections from human pancreatic tumors, these findings suggest that VIP-1 receptors may be expressed on the majority of neoplastic pancreatic duct epithelial cells in vivo. To initially test the hypothesis that expression of VIP-1 receptors plays an important role in the pathophysiology of human ductal pancreatic adenocarcinomas, we used reverse transcription-PCR with Southern blot hybridization to confirm expression of VIP-1 and VIP-2 receptor mRNA in the vast majority of 28 human ductal pancreatic adenocarcinomas. Based on the cellular heterogeneity of these tumors, we also assessed VIP receptor subtype expression in seven well-characterized, secretin-responsive cell lines derived from human ductal pancreatic adenocarcinomas. Only VIP-1 receptor mRNA was detected in all seven secretin-responsive cell lines. A half-maximal increase in intracellular cyclic AMP was obtained with 0.5-5 nM VIP in each of these cell lines, consistent with expression of high affinity VIP receptors. The ability of 1 microM, but not 1 nM, secretin to stimulate intracellular cyclic AMP generation in these cells was consistent with VIP-1 receptor expression. Interestingly, 100 pM, but not 1 microM, VIP stimulated significant growth of VIP-1 receptor-bearing Capan-2 cells both in the absence and presence of serum. Because VIP-1 receptors appear to be expressed in the majority of neoplastic pancreatic duct cell lines and VIP stimulates growth of VIP-1 receptor-bearing Capan-2 cells in vitro, this peptide may well play an important role in the pathophysiology of tumors expressing these receptors in vivo.