Digestive Diseases and Sciences

, Volume 59, Issue 6, pp 1180–1191 | Cite as

Cholecystokinin Mediates Progression and Metastasis of Pancreatic Cancer Associated with Dietary Fat

  • Gail L. Matters
  • Timothy K. Cooper
  • Christopher O. McGovern
  • Evan L. Gilius
  • Jiangang Liao
  • Brian M. Barth
  • Mark Kester
  • Jill P. Smith
Original Article



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.


Pancreatic cancer Devazepide Obesity High-fat diet CCK Metastasis 



Body mass index


Bovine serum albumin




Dulbecco’s modified Eagle’s medium/Ham’s F12


Dimethyl sulfoxide


Fetal bovine serum


Hematoxylin and eosin




Kilocalories per gram


National Cancer Institute


Phosphate-buffered saline


Quantitative real-time polymerase chain reaction




Relative quantity


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



  1. 1.
    Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013;63:11–30.PubMedCrossRefGoogle Scholar
  2. 2.
    Yadav D, Lowenfels AB. The epidemiology of pancreatitis and pancreatic cancer. Gastroenterology. 2013;144:1252–1261.PubMedCrossRefGoogle Scholar
  3. 3.
    Bracci PM. Obesity and pancreatic cancer: overview of epidemiologic evidence and biologic mechanisms. Mol Carcinog. 2012;51:53–63.PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Li D, Morris JS, Liu J, et al. Body mass index and risk, age of onset, and survival in patients with pancreatic cancer. JAMA. 2009;301:2553–2562.PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Roberts DL, Dive C, Renehan AG. Biological mechanisms linking obesity and cancer risk: new perspectives. Annu Rev Med. 2010;61:301–316.PubMedCrossRefGoogle Scholar
  6. 6.
    Aleman JO, Eusebi LH, Ricciardiello L, et al. Mechanisms of obesity-induced gastrointestinal neoplasia. Gastroenterology. 2014;146:357–373.PubMedCrossRefGoogle Scholar
  7. 7.
    White PB, Ziegler KM, Swartz-Basile DA, et al. Obesity, but not high-fat diet, promotes murine pancreatic cancer growth. J Gastrointest Surg. 2012;16:1680–1685.PubMedCrossRefGoogle Scholar
  8. 8.
    Wang F, Kumagai-Braesch M, Herrington MK, et al. Increased lipid metabolism and cell turnover of MiaPaCa2 cells induced by high-fat diet in an orthotopic system. Metabolism. 2009;58:1131–1136.PubMedCrossRefGoogle Scholar
  9. 9.
    Dawson DW, Hertzer K, Moro A, et al. High-fat, high-calorie diet promotes early pancreatic neoplasia in the conditional KrasG12D mouse model. Cancer Prev Res (Phila). 2013;6:1064–1073.CrossRefGoogle Scholar
  10. 10.
    Lashinger LM, Harrison LM, Rasmussen AJ, et al. Dietary energy balance modulation of Kras- and Ink4a/Arf+/−-driven pancreatic cancer: the role of insulin-like growth factor-I. Cancer Prev Res (Phila). 2013;6:1046–1055.CrossRefGoogle Scholar
  11. 11.
    Pisani P. Hyper-insulinaemia and cancer, meta-analyses of epidemiological studies. Arch Physiol Biochem. 2008;114:63–70.PubMedCrossRefGoogle Scholar
  12. 12.
    Stattin P, Bjor O, Ferrari P, et al. Prospective study of hyperglycemia and cancer risk. Diabetes Care. 2007;30:561–567.PubMedCrossRefGoogle Scholar
  13. 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
  14. 14.
    Philip B, Roland CL, Daniluk J, et al. A high-fat diet activates oncogenic Kras and COX2 to induce development of pancreatic ductal adenocarcinoma in mice. Gastroenterology. 2013;145:1449–1458.PubMedCrossRefGoogle Scholar
  15. 15.
    Dockray GJ. Cholecystokinin. Curr Opin Endocrinol Diabetes Obes. 2012;19:8–12.PubMedCrossRefGoogle Scholar
  16. 16.
    Solomon TE, Petersen H, Elashoff J, et al. Interaction of caerulein and secretin on pancreatic size and composition in rat. Am J Physiol. 1978;235:E714–E719.PubMedGoogle Scholar
  17. 17.
    Solomon TE, Vanier M, Morisset J. Cell site and time course of DNA synthesis in pancreas after caerulein and secretin. Am J Physiol. 1983;245:G99–G105.PubMedGoogle Scholar
  18. 18.
    Lehv M, Fitzgerald PJ. Pancreatic acinar cell regeneration. IV. Regeneration after resection. Am J Pathol. 1968;53:513–535.PubMedCentralPubMedGoogle Scholar
  19. 19.
    Elsasser HP, Adler G, Kern HF. Time course and cellular source of pancreatic regeneration following acute pancreatitis in the rat. Pancreas. 1986;1:421–429.PubMedCrossRefGoogle Scholar
  20. 20.
    Mainz DL, Black O, Webster PD. Hormonal control of pancreatic growth. J Clin Invest. 1973;52:2300–2304.PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Howatson AG, Carter DC. Pancreatic carcinogenesis-enhancement by cholecystokinin in the hamster-nitrosamine model. Br J Cancer. 1985;51:107–114.PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Carriere C, Young AL, Gunn JR, et al. Acute pancreatitis markedly accelerates pancreatic cancer progression in mice expressing oncogenic Kras. Biochem Biophys Res Commun. 2009;382:561–565.PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Guerra C, Schuhmacher AJ, Canamero M, et al. Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice. Cancer Cell. 2007;11:291–302.PubMedCrossRefGoogle Scholar
  24. 24.
    Smith JP, Rickabaugh CA, McLaughlin PJ, et al. Cholecystokinin receptors and PANC-1 human pancreatic cancer cells. Am J Physiol. 1993;265:G149–G155.PubMedGoogle Scholar
  25. 25.
    Smith JP, Liu G, Soundararajan V, et al. Identification and characterization of CCK-B/gastrin receptors in human pancreatic cancer cell lines. Am J Physiol. 1994;266:R277–R283.PubMedGoogle Scholar
  26. 26.
    Weinberg DS, Ruggeri B, Barber MT, et al. Cholecystokinin A and B receptors are differentially expressed in normal pancreas and pancreatic adenocarcinoma. J Clin Invest. 1997;100:597–603.PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Smith JP, Solomon TE, Bagheri S, et al. Cholecystokinin stimulates growth of human pancreatic adenocarcinoma SW-1990. Dig Dis Sci. 1990;35:1377–1384.PubMedCrossRefGoogle Scholar
  28. 28.
    Smith JP, Kramer ST, Solomon TE. CCK stimulates growth of six human pancreatic cancer cell lines in serum-free medium. Regul Pept. 1991;32:341–349.PubMedCrossRefGoogle Scholar
  29. 29.
    Smith JP, Kramer S, Bagheri S. Effects of a high-fat diet and L364,718 on growth of human pancreas cancer. Dig Dis Sci. 1990;35:726–732.PubMedCrossRefGoogle Scholar
  30. 30.
    Corbett TH, Roberts BJ, Leopold WR, et al. Induction and chemotherapeutic response of two transplantable ductal adenocarcinomas of the pancreas in C57BL/6 mice. Cancer Res. 1984;44:717–726.PubMedGoogle Scholar
  31. 31.
    Nikfarjam M, Yeo D, He H, et al. Comparison of two syngeneic orthotopic murine models of pancreatic adenocarcinoma. J Invest Surg. 2013;26:352–359.PubMedCrossRefGoogle Scholar
  32. 32.
    Matters GL, Harms JF, McGovern CO, et al. Growth of human pancreatic cancer is inhibited by down-regulation of gastrin gene expression. Pancreas. 2009;38:e151–e161.PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Barrachina MD, Martinez V, Wang L, et al. Synergistic interaction between leptin and cholecystokinin to reduce short-term food intake in lean mice. Proc Natl Acad Sci USA. 1997;94:10455–10460.PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Carrillo J, Garcia-Aragoncillo E, Azorin D, et al. Cholecystokinin down-regulation by RNA interference impairs Ewing tumor growth. Clin Cancer Res. 2007;13:2429–2440.PubMedCrossRefGoogle Scholar
  35. 35.
    Cummings DE, Overduin J. Gastrointestinal regulation of food intake. J Clin Invest. 2007;117:13–23.PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Surwit RS, Feinglos MN, Rodin J, et al. Differential effects of fat and sucrose on the development of obesity and diabetes in C57BL/6J and A/J mice. Metabolism. 1995;44:645–651.PubMedCrossRefGoogle Scholar
  37. 37.
    Grabowska AM, Watson SA. Role of gastrin peptides in carcinogenesis. Cancer Lett. 2007;257:1–15.PubMedCrossRefGoogle Scholar
  38. 38.
    Lewis LD, Williams JA. Regulation of cholecystokinin secretion by food, hormones, and neural pathways in the rat. Am J Physiol. 1990;258:G512–G518.PubMedGoogle Scholar
  39. 39.
    Smith JP, Solomon TE. Cholecystokinin and pancreatic cancer: the chicken or the egg? Am J Physiol Gastrointest Liver Physiol. 2014;306:G91–G101.PubMedCrossRefGoogle Scholar
  40. 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
  41. 41.
    Lavine JA, Raess PW, Stapleton DS, et al. Cholecystokinin is up-regulated in obese mouse islets and expands beta-cell mass by increasing beta-cell survival. Endocrinology. 2010;151:3577–3588.PubMedCentralPubMedCrossRefGoogle Scholar
  42. 42.
    Zyromski NJ, Mathur A, Pitt HA, et al. Obesity potentiates the growth and dissemination of pancreatic cancer. Surgery. 2009;146:258–263.PubMedCrossRefGoogle Scholar
  43. 43.
    Weis S, Cui J, Barnes L, et al. Endothelial barrier disruption by VEGF-mediated Src activity potentiates tumor cell extravasation and metastasis. J Cell Biol. 2004;167:223–229.PubMedCentralPubMedCrossRefGoogle Scholar
  44. 44.
    Silha JV, Krsek M, Sucharda P, et al. Angiogenic factors are elevated in overweight and obese individuals. Int J Obes (Lond). 2005;29:1308–1314.CrossRefGoogle Scholar
  45. 45.
    Wey JS, Fan F, Gray MJ, et al. Vascular endothelial growth factor receptor-1 promotes migration and invasion in pancreatic carcinoma cell lines. Cancer. 2005;104:427–438.PubMedCrossRefGoogle Scholar
  46. 46.
    Korc M. Pathways for aberrant angiogenesis in pancreatic cancer. Mol Cancer. 2003;2:8.PubMedCentralPubMedCrossRefGoogle Scholar
  47. 47.
    Takahashi H, Shibuya M. The vascular endothelial growth factor (VEGF)/VEGF receptor system and its role under physiological and pathological conditions. Clin Sci (Lond). 2005;109:227–241.CrossRefGoogle Scholar
  48. 48.
    Yang AD, Camp ER, Fan F, et al. Vascular endothelial growth factor receptor-1 activation mediates epithelial to mesenchymal transition in human pancreatic carcinoma cells. Cancer Res. 2006;66:46–51.PubMedCrossRefGoogle Scholar
  49. 49.
    Seo Y, Baba H, Fukuda T, et al. High expression of vascular endothelial growth factor is associated with liver metastasis and a poor prognosis for patients with ductal pancreatic adenocarcinoma. Cancer. 2000;88:2239–2245.PubMedCrossRefGoogle Scholar
  50. 50.
    Berna MJ, Jensen RT. Role of CCK/gastrin receptors in gastrointestinal/metabolic diseases and results of human studies using gastrin/CCK receptor agonists/antagonists in these diseases. Curr Top Med Chem. 2007;7:1211–1231.PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Gail L. Matters
    • 1
  • Timothy K. Cooper
    • 2
    • 3
  • Christopher O. McGovern
    • 4
  • Evan L. Gilius
    • 4
  • Jiangang Liao
    • 5
  • Brian M. Barth
    • 6
  • Mark Kester
    • 6
  • Jill P. Smith
    • 4
    • 7
  1. 1.Department of Biochemistry and Molecular Biology, College of MedicineThe Pennsylvania State UniversityHersheyUSA
  2. 2.Department of Comparative Medicine, College of MedicineThe Pennsylvania State UniversityHersheyUSA
  3. 3.Department of Pathology, College of MedicineThe Pennsylvania State UniversityHersheyUSA
  4. 4.Department of Medicine, College of MedicineThe Pennsylvania State UniversityHersheyUSA
  5. 5.Department of Public Health Sciences, College of MedicineThe Pennsylvania State UniversityHersheyUSA
  6. 6.Department of Pharmacology, College of MedicineThe Pennsylvania State UniversityHersheyUSA
  7. 7.Department of MedicineGeorgetown University HospitalWashingtonUSA

Personalised recommendations