Pancreatic Cancer-Derived Exosomes Cause Paraneoplastic ?-cell Dysfunction.

ABSTRACT: Pancreatic cancer frequently causes diabetes. We recently proposed adrenomedullin as a candidate mediator of pancreatic ?-cell dysfunction in pancreatic cancer. How pancreatic cancer-derived adrenomedullin reaches ? cells remote from the cancer to induce ?-cell dysfunction is unknown. We tested a novel hypothesis that pancreatic cancer sheds adrenomedullin-containing exosomes into circulation, which are transported to ? cells and impair insulin secretion.We characterized exosomes from conditioned media of pancreatic cancer cell lines (n = 5) and portal/peripheral venous blood of patients with pancreatic cancer (n = 20). Western blot analysis showed the presence of adrenomedullin in pancreatic cancer-exosomes. We determined the effect of adrenomedullin-containing pancreatic cancer exosomes on insulin secretion from INS-1 ? cells and human islets, and demonstrated the mechanism of exosome internalization into ? cells. We studied the interaction between ?-cell adrenomedullin receptors and adrenomedullin present in pancreatic cancer-exosomes. In addition, the effect of adrenomedullin on endoplasmic reticulum (ER) stress response genes and reactive oxygen/nitrogen species generation in ? cells was shown.Exosomes were found to be the predominant extracellular vesicles secreted by pancreatic cancer into culture media and patient plasma. Pancreatic cancer-exosomes contained adrenomedullin and CA19-9, readily entered ? cells through caveolin-mediated endocytosis or macropinocytosis, and inhibited insulin secretion. Adrenomedullin in pancreatic cancer exosomes interacted with its receptor on ? cells. Adrenomedullin receptor blockade abrogated the inhibitory effect of exosomes on insulin secretion. ? cells exposed to adrenomedullin or pancreatic cancer exosomes showed upregulation of ER stress genes and increased reactive oxygen/nitrogen species.Pancreatic cancer causes paraneoplastic ?-cell dysfunction by shedding adrenomedullin(+)/CA19-9(+) exosomes into circulation that inhibit insulin secretion, likely through adrenomedullin-induced ER stress and failure of the unfolded protein response.

SUBMITTER: Javeed N 

PROVIDER: S-EPMC4383684 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature