Interaction between pancreatic cancer and beta cells : intraislet significance of islet amyloid polypeptide

Sammanfattning: Introduction. Mutual influences have been found between exocrine pancreatic cancer and the endocrine pancreatic islets. In laboratory animals, induction and growth of pancreatic cancer are affected by the endocrine pancreas. Conversely, abnormalities of the endocrine pancreas are frequently seen in mammals with pancreatic cancer. Islet amyloid polypeptide (IAPP) is produced in pancreatic ß-cells and cosecreted with insulin. The intraislet significance of IAPP is uncertain. IAPP plasma levels are elevated in pancreatic cancer patients. The direct effect of exocrine pancreatic cancer on IAPP secretion is unknown. Aims. The present studies were undertaken in vitro in order to investigate the effects of isolated rat pancreatic islets on the growth and metabolism of pancreatic cancer cells (Study I), the effects of pancreatic cancer cells on insulin and IAPP secretion (Studies II & III), and the paracrine effects of IAPP in the endocrine islets (Studies IV-VI). Methods. Model 1: Isolated rat pancreatic islets and human pancreatic cancer cells were cocultured in two-compartment culture plates (Studies I & II). Model 2: Isolated islets were incubated in culture media conditioned by pancreatic cancer cells (Study III). Model 3: Isolated islets were incubated with IAPP, IAPP inhibitors, and other islet regulators in Krebs-Ringer bicarbonate (KRB) buffers (Studies IV-VI). Results. Proliferation and glucose utilization of a human pancreatic cancer cell line (HPAF) were increased by cocultured islets. Growth and glucose utilization of HPAF cells were also increased by different concentrations of exogenous insulin. One insulin concentration used was comparable to the insulin secretion seen in the coculture experiments. The secretion of insulin and IAPP was decreased when islets were cocultured with human pancreatic (Panc-1 and HPAF) and colonic (HT-29) cancer cell lines. The IAPP-to-insulin molar ratio was increased in the islets by coculture with Panc-1 or HPAF cells but not with HT-29 cells. Abnormal insulin and IAPP secretion and an increased IAPP/insulin ratio were also seen when the islets were incubated in culture media conditioned by Panc-1 and HPAF cells. Insulin secretion induced by 15 mM L-arginine or 16.7-22.2 mM glucose was increased by IAPP antiserum and an IAPP antagonist (IAPP8-37) . Arginine-stimulated secretion of glucagon and somatostatin was increased by IAPP antiserum and/or IAPP8-37 as well. The arginine-stimulated secretion of insulin and glucagon was further enhanced when IAPP antiserum or IAPP8-37 was combined with somatostatin antiserum. However, at basal glucose (5.6 mM), IAPP antiserum and IAPP8-37 did not change the insulin secretion induced by 30 mM KC1 Exogenous IAPP enhanced the inhibitory effect of somatostatin on arginine-induced insulin secretion at both 4.4 and 30 mM KC1 In islets pretreated with pertussis toxin (PTX), the IAPP-somatostatin combination did not show any inhibitory effects on the arginine-induced insulin secretion. In addition, IAPP enhanced the inhibitory effect of somatostatin on insulin secretion induced by 25 µM forskolin. Conclusions. The growth and glucose utilization of human pancreatic cancer cells are enhanced by isolated rat pancreatic islets. The trophic effects of pancreatic islets may be mediated by insulin release from the islet ß-cells Human pancreatic cancer cells attenuate and dissociate the secretion of LAPP and insulin. IAPP inhibits insulin, glucagon, and somatostatin secretion from isolated rat pancreatic islets. IAPP cooperates with somatostatin in the regulation of insulin and glucagon secretion. Inside ß-cells IAPP regulates multiple steps in the signal transduction for insulin release. The effects of IAPP are mediated by PTX-sensitive regulatory G-proteins.