Abstract

1504 Background: Pancreatic cancer is the 4th leading cause of cancer death in both men and women in the U.S. Increased obesity has emerged as a risk factor for pancreatic cancer. Calorie restriction (CR), a dietary strategy that prevents or reverses obesity, has significant anti-cancer effects in a variety of tumor types and in both spontaneous and chemically-induced tumors. We have found in the K5.COX-2 transgenic mouse model of pancreatitis-driven pancreatic cancer that CR significantly protects from spontaneous pancreatic lesion formation as compared to the overweight and obese groups. Also, CR mice had significantly reduced serum IGF-1 levels and pro-inflammatory cytokine levels as compared to ad libitum fed (AL) and high fat (HF) fed mice. We hypothesized that decreased serum IGF-1 levels were responsible for the decreased tumor burden. Methods: Orthotopic injections were performed on 6–8 week old Liver-specific IGF-1- Deficient (LID) and control mice (FVB/N and floxed IGF-1) with pancreatic tumor cells (JC101) derived from a transgenic K5.COX-2 animal. Tumors and pancreata were harvested and weighed 28 days after tumor injection. Results: LID mice exhibited significantly reduced tumor burden (0.23±0.04) than either the floxed IGF-1 control (0.71±0.10) or FVB/N wild-type animals (0.71±0.04) following 28 days of growth. In addition to a reduction in serum IGF-1 in the LID mice, we also found a substantial decrease in serum levels of a panel of pro-inflammatory cytokines such as IFN-g, IL-1b, IL-4, IL-5, IL-10, IL-12, and TNF-a as compared to sera of control animals. Furthermore, we saw reduced proliferation and microvessel density in the tumor tissue of LID animals compared to controls by immunohistochemical staining. Conclusions: Using a model of pancreatitis-induced or orthotopically injected pancreatic tumorigenesis, our findings indicate that either transgenic manipulation or diet modulation of serum IGF-1 can alter the development of pancreatic cancer. Moreover, our findings suggest a strong link between expression of IGF-1 and pro-inflammatory cytokines in response to CR and the prevention of tumor growth. This could have direct implications for the prevention and control of pancreatic tumors due to chronic inflammation and/or obesity. No significant financial relationships to disclose.