CCK1 and CCK2 Receptors Are Expressed on Pancreatic Stellate Cells and Induce Collagen Production

Abstract

The gastrointestinal hormone cholecystokinin (CCK) can induce acute pancreatitis in rodents through its action on acinar cells. Treatment with CCK, in combination with other agents, represents the most commonly used model to induce experimental chronic pancreatitis. Pancreatic stellate cells (PSC) are responsible for pancreatic fibrosis and therefore play a predominant role in the genesis of chronic pancreatitis. However, it is not known whether PSC express CCK receptors. Using real time PCR techniques, we demonstrate that CCK1 and CCK2 receptors are expressed on rat PSC. Interestingly both CCK and gastrin significantly induced type I collagen synthesis. Moreover, both inhibit proliferation. These effects are comparable with TGF-␤-stimulated PSC. Furthermore, the natural agonists CCK and gastrin induce activation of pro-fibrogenic pathways Akt, ERK, and Src. Using specific CCK1 and CCK2 receptor (CCK2R) inhibitors, we found that Akt activation is mainly mediated by CCK2R. Akt activation by CCK and gastrin could be inhibited by the PI3K inhibitor wortmannin. Activation of ERK and the downstream target Elk-1 could be inhibited by the MEK inhibitor U0126. These data suggest that CCK and gastrin have direct activating effects on PSC, are able to induce collagen synthesis in these cells, and therefore appear to be important regulators of pancreatic fibrogenesis. Furthermore, similar to TGF-␤, both CCK and gastrin inhibit proliferation in PSC.

Ormeloxifene Suppresses Desmoplasia and Enhances Sensitivity of Gemcitabine in Pancreatic Cancer

“…On day 2, the culture inserts were placed into 6-well plates containing Panc-1 cells (0.8 × 10 6 cells/well), followed by treatment with ORM (10 µM) and GEM (100 nM) and incubated up to 2 days in DMEM medium. As previous studies have shown TGF-β to be a potent inducer of epithelial-mesenchymal transition (EMT) in several cancer cells including pancreatic cancer cells (26, 27), we used recombinant TGF-β (2 ng/ml) to stimulate the stromal cells as a mediator of PSC-induced EMT in cells.…”

The role of pancreatic stellate cells in pancreatic cancer

“…An additional role in exocrine function has been demonstrated, whereby the gastrointestinal hormone cholecystokinin (CCK) induces acetylcholine secretion by PaSCs, which in turn stimulates amylase secretion by acinar cells [20]. Furthermore CCK has been shown to have direct activating effect on PaSCs, and induces collagen synthesis [21].…”

Cholecystokinin Receptor Antagonist Halts Progression of Pancreatic Cancer Precursor Lesions and Fibrosis in Mice

“…21 CCK receptors have also been identified on pancreatic stellate cells and when stimulated with CCK, these cells produce collagen. 22,23 Therefore, it has been proposed that CCK plays an important role in pancreatic carcinogenesis and the fibrosis associated with pancreatic cancer. 24 …”