Insulin, Leptin, and Tumoral Adipocytes Promote Murine Pancreatic Cancer Growth
Patrick B. White*, Eben M. True, Kathryn M. Dalbec, Sue Wang, Deborah a. Swartz-Basile, Henry a. Pitt, Nicholas J. Zyromski
Department of Surgery, Indiana University School of Medicine, Indianapolis, IN
Background: Obesity has been associated with an increased incidence and enhanced progression of human pancreatic cancer. We previously developed a model in congenitally obese, leptin-deficient and leptin-resistant, mice where pancreatic cancers grew faster, metastasized more often, and shortened survival compared to lean mice. In this model, obese mice had more adipocytes in the tumor microenvironment, and tumor weight correlated with body weight and insulin, but not with leptin. To further understand these associations, we developed a diet-induced overweight model of murine pancreatic cancer. In this model we tested the hypothesis that overweight mice would have increased serum insulin and leptin levels as well as larger pancreatic tumors with more adipocytes. Methods: Thirty lean C57 female mice were fed either a control 10% fat (n=10) or a 60% fat diet (n=20) starting at 6 weeks of age. At 11 weeks, all mice were inoculated with 2.5x105 PAN02 murine pancreatic cancer cells. After 6 weeks, the mice were injected with BRDU, and tumors that developed in 18 animals as well as sera were harvested. The mice were categorized as Lean or Overweight if they weighed less or more than the mean final weight of the 60% fat diet animals (23.1g). Tumors were stained for BRDU and H&E to measure proliferation and adipocyte infiltration, respectively. Two observers blinded to animal weight assessed these parameters in 10 high-powered fields of each tumor. Serum levels of insulin and leptin were determined by RIA and ELISA, respectively. Data were analyzed by Student’s t-test, Wilcoxian rank-sum, or Pearson correlations as appropriate.Results: All mice survived until harvest, and no metastases were observed. Animal and tumor weight as well as serum insulin and leptin data are presented in the table. Significant correlations were observed between mouse and tumor weight (R=0.56, p<0.02), mouse weight and serum leptin (R=0.64, p<0.001), as well as tumor adipocytes and BRDU (R=0.59, p<0.01).Conclusion: These data suggest that 1) mouse weight correlates with pancreatic tumor size and serum leptin, 2) overweight mice have larger tumors as well as elevated serum insulin and leptin, and 3) tumor adipocytes correlate with tumor cell proliferation. We conclude that overweight mice with increased serum insulin and leptin as well as adipocytes in the tumor microenvironment have enhanced pancreatic cancer growth.
| Mouse Weight (g) | Tumor Weight (g) | Insulin (ng/ml) | Leptin (ng/ml) | |
| Lean | 21.2±0.2 | 0.5±0.2 | 0.18±0.02 | 1.4±0.2 |
| Overweight | 25.0±0.4* | 1.3±0.3* | 0.48±0.21* | 3.1±0.7* |
*p≤0.05 vs. Lean
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