Cholecystokinin receptor antagonist halts progression of pancreatic cancer precursor lesions and fibrosis in mice

• Published in: Pancreas Vol. 43; no. 7; pp. 1050 - 1059
• Main Authors: Smith, Jill P, Cooper, Timothy K, McGovern, Christopher O, Gilius, Evan L, Zhong, Qing, Liao, Jiangang, Molinolo, Alfredo A, Gutkind, J Silvio, Matters, Gail L
• Format: Journal Article
• Language: English
• Published: United States 01-10-2014
• Subjects: Animals; Carcinoma in Situ - chemistry; Carcinoma in Situ - drug therapy; Carcinoma in Situ - pathology; Carcinoma in Situ - prevention & control; Cholecystokinin - physiology; Disease Progression; Drug Screening Assays, Antitumor; Fibrosis; Humans; Mice; Mice, Transgenic; Pancreas - chemistry; Pancreas - drug effects; Pancreas - pathology; Pancreatic Neoplasms - chemistry; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - pathology; Pancreatic Neoplasms - prevention & control; Pancreatitis - prevention & control; Precancerous Conditions - drug therapy; Precancerous Conditions - metabolism; Precancerous Conditions - pathology; Proglumide - pharmacology; Proglumide - therapeutic use; Random Allocation; Receptor, Cholecystokinin A - analysis; Receptor, Cholecystokinin A - antagonists & inhibitors; Receptor, Cholecystokinin B - analysis; Receptor, Cholecystokinin B - antagonists & inhibitors
• ISSN: 0885-3177; 1536-4828
• DOI: 10.1097/MPA.0000000000000194

Exogenous administration of cholecystokinin (CCK) induces hypertrophy and hyperplasia of the pancreas with an increase in DNA content. We hypothesized that endogenous CCK is involved in the malignant progression of pancreatic intraepithelial neoplasia (PanIN) lesions and the fibrosis associated with pancreatic cancer.
The presence of CCK receptors in early PanIN lesions was examined by immunohistochemistry in mouse and human pancreas. Pdx1-Cre/LSL-Kras transgenic mice were randomized to receive either untreated drinking water or water supplemented with a CCK receptor antagonist (proglumide, 0.1 mg/mL). Pancreas from the mice were removed and examined histologically for number and grade of PanINs after 1, 2, or 4 months of antagonist therapy.
Both CCK-A and CCK-B receptors were identified in early stage PanINs from mouse and human pancreas. The grade of PanIN lesions was reversed, and progression to advanced lesions arrested in mice treated with proglumide compared with the controls (P = 0.004). Furthermore, pancreatic fibrosis was significantly reduced in antagonist-treated animals compared with vehicle (P < 0.001).
These findings demonstrate that endogenous CCK is in part responsible for the development and progression of pancreatic cancer. The use of CCK receptor antagonists may have a role in cancer prophylaxis in high-risk subjects and may reduce fibrosis in the microenvironment.