Abstract | OBJECTIVES: METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.
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Authors | Jill P Smith, Timothy K Cooper, Christopher O McGovern, Evan L Gilius, Qing Zhong, Jiangang Liao, Alfredo A Molinolo, J Silvio Gutkind, Gail L Matters |
Journal | Pancreas
(Pancreas)
Vol. 43
Issue 7
Pg. 1050-9
(Oct 2014)
ISSN: 1536-4828 [Electronic] United States |
PMID | 25058882
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Receptor, Cholecystokinin A
- Receptor, Cholecystokinin B
- Cholecystokinin
- Proglumide
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Topics |
- Animals
- Carcinoma in Situ
(chemistry, drug therapy, pathology, prevention & control)
- Cholecystokinin
(physiology)
- Disease Progression
- Drug Screening Assays, Antitumor
- Fibrosis
- Humans
- Mice
- Mice, Transgenic
- Pancreas
(chemistry, drug effects, pathology)
- Pancreatic Neoplasms
(chemistry, drug therapy, pathology, prevention & control)
- Pancreatitis
(prevention & control)
- Precancerous Conditions
(drug therapy, metabolism, pathology)
- Proglumide
(pharmacology, therapeutic use)
- Random Allocation
- Receptor, Cholecystokinin A
(analysis, antagonists & inhibitors)
- Receptor, Cholecystokinin B
(analysis, antagonists & inhibitors)
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