title: Cholecystokinin mediates progression and metastasis of pancreatic cancer associated with dietary fat.
abstract: BACKGROUND
  Obesity and dietary fat are associated with increased risk of several malignancies including pancreatic cancer. The incidence of pancreatic cancer is increased in countries that consume diets high in fat.
  
  
  OBJECTIVE
  The purpose of this study was to assess the relationship and mechanism of action between dietary fat and endogenous cholecystokinin (CCK) on pancreatic tumor growth and metastasis in an immunocompetent animal model.
  
  
  METHODS
  C57BL/6 mice were placed on regular, low-fat, or high-fat diets for 8 weeks before establishment of Panc-02 orthotopic pancreatic tumors. Mice were then treated with a CCK-A receptor antagonist, devazepide, or vehicle for an additional 2.5 weeks. Pancreas tumors were weighed and metastases counted. Blood CCK levels were measured by radioimmunoassay (RIA). Tissues were examined histologically and studied for genes associated with metastasis by RT-PCR array. Effects of the CCK antagonist on Panc-02 cells invasiveness was assessed in a Matrigel invasion assay.
  
  
  RESULTS
  Mice that received the high-fat diet had larger tumors and tenfold higher serum CCK levels by RIA compared to normal diet controls (p < 0.01). Pancreatic tumors in high-fat diet mice treated with the antagonist had fewer intravascular tumor emboli and metastases compared to controls. The reduction in tumor emboli correlated with decreased vascular endothelial growth factor-A (VEGF-A) expression in tumors (p < 6 × 10(-9)). In vitro invasiveness of Panc-02 cells also was reduced by CCK-A receptor antagonist treatment (p = 1.33 × 10(-6)).
  
  
  CONCLUSIONS
  CCK is a mediator of dietary fat-associated pancreatic cancer. CCK is also involved in the invasiveness of pancreatic tumors through a mechanism involving VEGF-A.
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, The Pennsylvania State University, Hershey, PA, 17033, USA.
authors.forename: Gail L
authors.initials: GL
authors.lastname: Matters
authors.forename: Timothy K
authors.initials: TK
authors.lastname: Cooper
authors.forename: Christopher O
authors.initials: CO
authors.lastname: McGovern
authors.forename: Evan L
authors.initials: EL
authors.lastname: Gilius
authors.forename: Jiangang
authors.initials: J
authors.lastname: Liao
authors.forename: Brian M
authors.initials: BM
authors.lastname: Barth
authors.forename: Mark
authors.initials: M
authors.lastname: Kester
authors.forename: Jill P
authors.initials: JP
authors.lastname: Smith
mesh_terms: D000818:Animals; D001786:Blood Glucose; D045744:Cell Line, Tumor; D002766:Cholecystokinin / Q000378:metabolism*; D020109:Devazepide / Q000494:pharmacology; D004041:Dietary Fats / Q000008:administration & dosage / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D004617:Embolism / Q000517:prevention & control; D006727:Hormone Antagonists / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis / Q000517:prevention & control; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D011863:Radioimmunoassay
chemical_list: D001786:Blood Glucose; D004041:Dietary Fats; D006727:Hormone Antagonists; D002766:Cholecystokinin; D020109:Devazepide