Pancreatic cancer–derived exosomes cause paraneoplastic β-cell dysfunction
Clinical Cancer Research, 2015•AACR
Purpose: Pancreatic cancer frequently causes diabetes. We recently proposed
adrenomedullin as a candidate mediator of pancreatic β-cell dysfunction in pancreatic
cancer. How pancreatic cancer–derived adrenomedullin reaches β cells remote from the
cancer to induce β-cell dysfunction is unknown. We tested a novel hypothesis that
pancreatic cancer sheds adrenomedullin-containing exosomes into circulation, which are
transported to β cells and impair insulin secretion. Experimental Methods: We characterized …
adrenomedullin as a candidate mediator of pancreatic β-cell dysfunction in pancreatic
cancer. How pancreatic cancer–derived adrenomedullin reaches β cells remote from the
cancer to induce β-cell dysfunction is unknown. We tested a novel hypothesis that
pancreatic cancer sheds adrenomedullin-containing exosomes into circulation, which are
transported to β cells and impair insulin secretion. Experimental Methods: We characterized …
Abstract
Purpose: Pancreatic cancer frequently causes diabetes. We recently proposed adrenomedullin as a candidate mediator of pancreatic β-cell dysfunction in pancreatic cancer. How pancreatic cancer–derived adrenomedullin reaches β cells remote from the cancer to induce β-cell dysfunction is unknown. We tested a novel hypothesis that pancreatic cancer sheds adrenomedullin-containing exosomes into circulation, which are transported to β cells and impair insulin secretion.
Experimental Methods: 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 β cells and human islets, and demonstrated the mechanism of exosome internalization into β cells. We studied the interaction between β-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 β cells was shown.
Results: 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 β cells through caveolin-mediated endocytosis or macropinocytosis, and inhibited insulin secretion. Adrenomedullin in pancreatic cancer exosomes interacted with its receptor on β cells. Adrenomedullin receptor blockade abrogated the inhibitory effect of exosomes on insulin secretion. β cells exposed to adrenomedullin or pancreatic cancer exosomes showed upregulation of ER stress genes and increased reactive oxygen/nitrogen species.
Conclusions: Pancreatic cancer causes paraneoplastic β-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. Clin Cancer Res; 21(7); 1722–33. ©2014 AACR.
See related commentary by Korc, p. 1508
AACR