Cholecystokinin Mediates Progression and Metastasis of Pancreatic Cancer Associated with Dietary Fat
- 361 Downloads
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.
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.
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.
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).
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.
KeywordsPancreatic cancer Devazepide Obesity High-fat diet CCK Metastasis
Body mass index
Bovine serum albumin
Dulbecco’s modified Eagle’s medium/Ham’s F12
Fetal bovine serum
Hematoxylin and eosin
Kilocalories per gram
National Cancer Institute
Quantitative real-time polymerase chain reaction
Vascular endothelial growth factor-A
Vascular endothelial growth factor receptor
This work was funded by the NIH R01 CA117926 grant to JPS. We recognize additional support from The V-Foundation for Cancer Research to M.K. and the Robert Sullivan Foundation to J.P.S. We appreciate the technical services of Michael Stephan and Evan Shirey from Messiah College, Grantham, PA. The expert technical assistance of Weifang Lin, Department of Comparative Medicine, Rob Brucklacher in the Functional Genomics Core, Wade Edris in the Microscopy Imaging Core, and Dr. Bruce Stanley, Director of Scientific Programs, Section of Research Resources, Pennsylvania State University College of Medicine, are also appreciated. Core Facility services and instruments used in this project were funded, in part, under a grant with the Pennsylvania Department of Health using Tobacco Settlement Funds. This department specifically disclaims responsibility for any analyses, interpretations, or conclusions.
Conflict of interest
- 13.Stolzenberg-Solomon RZ, Limburg P, Pollak M, et al. Insulin-like growth factor (IGF)-1, IGF-binding protein-3, and pancreatic cancer in male smokers. Cancer Epidemiol Biomark Prev. 2004;13:438–444.Google Scholar
- 40.Shiratori K, Takeuchi T, Satake K, et al. Clinical evaluation of oral administration of a cholecystokinin-A receptor antagonist (loxiglumide) to patients with acute, painful attacks of chronic pancreatitis: a multicenter dose-response study in Japan. Pancreas. 2002;25:e1–e5.PubMedCrossRefGoogle Scholar