Cholecystokinin receptor antagonist induces pancreatic stellate cell plasticity rendering the tumor microenvironment less oncogenic

CCK receptors are expressed on pancreatic cancer epithelial cells and blockade with receptor antagonists decreases tumor growth. Activated pancreatic stellate cells or myofibroblasts have also been described to express CCK receptors, but the contribution of this novel pathway in fibrosis of the pancreatic cancer microenvironment has not been studied. We examined the effects of the CCK peptide agonist and CCK receptor antagonists on activation, proliferation, collagen deposition, and migration in both murine and human PSCs. CCK receptor expression and subtype was examined by qRT-PCR and western analysis. Collagen production by activated PSCs was analyzed by mass spectroscopy and western blot. Mouse and human PSCs expressed both CCK-A and CCK-B receptors by qRT-PCR. Migration of activated PSCs was prevented in vitro by proglumide and the CCK-B receptor antagonist, L365,260, but not by the CCK-A receptor antagonist L365,718. Proglumide effectively decreased the expression of fibrosis-associated genes and collagen-associated proteins. Components of fibrosis, including hydroxyproline and proline levels were significantly reduced in PSC treated with proglumide compared to controls. CCK peptide stimulated mouse and human PSC proliferation and this effect was blocked by proglumide. These investigations demonstrate that targeting the CCK-B receptor signaling pathway with proglumide may alter plasticity of PSC rendering them more quiescent and leading to a decrease in fibrosis in the pancreatic cancer microenvironment.