title: Cholecystokinin receptor antagonist halts progression of pancreatic cancer precursor lesions and fibrosis in mice.
abstract: OBJECTIVE
  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.
  
  
  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.
authors: From the *National Institute of Diabetes and Digestive and Kidney Disease, The National Institutes of Health, Bethesda, MD; Departments of †Medicine, ‡Comparative Medicine and Pathology, §Public Health Sciences, and ∥Biochemistry and Molecular Biology, The Pennsylvania State University, College of Medicine, Hershey, PA; and ¶National Institute of Dental and Craniofacial Research, The National Institutes of Health, Bethesda, MD.
authors: Jill P
authors: JP
authors: Smith
authors: Timothy K
authors: TK
authors: Cooper
authors: Christopher O
authors: CO
authors: McGovern
authors: Evan L
authors: EL
authors: Gilius
authors: Qing
authors: Q
authors: Zhong
authors: Jiangang
authors: J
authors: Liao
authors: Alfredo A
authors: AA
authors: Molinolo
authors: J Silvio
authors: JS
authors: Gutkind
authors: Gail L
authors: GL
authors: Matters
mesh_terms: D000818:Animals; D002278:Carcinoma in Situ / Q000737:chemistry / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control*; D002766:Cholecystokinin / Q000502:physiology; D018450:Disease Progression; D004354:Drug Screening Assays, Antitumor; D005355:Fibrosis; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D010179:Pancreas / Q000737:chemistry / Q000187:drug effects* / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000737:chemistry / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control*; D010195:Pancreatitis / Q000517:prevention & control; D011230:Precancerous Conditions / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011377:Proglumide / Q000494:pharmacology / Q000627:therapeutic use*; D011897:Random Allocation; D043886:Receptor, Cholecystokinin A / Q000032:analysis / Q000037:antagonists & inhibitors*; D043887:Receptor, Cholecystokinin B / Q000032:analysis / Q000037:antagonists & inhibitors*
chemical_list: D043886:Receptor, Cholecystokinin A; D043887:Receptor, Cholecystokinin B; D002766:Cholecystokinin; D011377:Proglumide