Vasoactive intestinal peptide (VIP) stimulates in vitro growth of VIP-1 receptor-bearing human pancreatic adenocarcinoma-derived cells.
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.
Jiang
S
S
University of Cincinnati Medical Center, Ohio 45267-0595, USA.
Kopras
E
E
McMichael
M
M
Bell
R H
RH
Ulrich
C D
CD
D000230:Adenocarcinoma / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology; D015139:Blotting, Southern; D002455:Cell Division / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D009363:Neoplasm Proteins / Q000378:metabolism*; D010179:Pancreas / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled; D011964:Receptors, Gastrointestinal Hormone / Q000378:metabolism; D018005:Receptors, Vasoactive Intestinal Peptide / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014660:Vasoactive Intestinal Peptide / Q000494:pharmacology*
D009363:Neoplasm Proteins; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D011964:Receptors, Gastrointestinal Hormone; D018005:Receptors, Vasoactive Intestinal Peptide; C029937:secretin receptor; D014660:Vasoactive Intestinal Peptide; D000242:Cyclic AMP