Abstract A102: Genetic reduction of circulating IGF-1 decreases growth of pancreatic tumors in an orthotopic transplant model

Authors

Laura Lashinger

Published

January 1, 2010

Abstract

Abstract Pancreatic cancer is the 4th deadliest cancer in the U.S. Obesity has emerged as a significant and modifiable risk factor for pancreatic cancer. Calorie restriction (CR) is an anti-obesity intervention that has been shown in many model systems to have potent anticancer effects. Levels of bioavailable insulin-like growth factor (IGF)-1, an established mitogen in a variety of cancer cell lines, increase in response to positive energy balance and decrease with CR. We hypothesized that the genetic reduction of circulating IGF-1 levels seen in liver-specific IGF-1-deficient (LID) mice would diminish the tumor burden of orthotopically transplanted pancreatic cancer cells, similar to CR, while administration of exogenous IGF-1 would restore the tumor burden. To test this hypothesis, mouse pancreatic cancer cells (JC101, derived from our BK5-COX-2 transgenic mouse model of spontaneous pancreatic cancer) were orthotopically transplanted in LID and littermate control (LC) mice. LID mice were also randomized to receive Alzet miniature osmotic pumps (implanted subcutaneously) continuously infusing either vehicle (n=8) or 1 µg/hr of recombinant human IGF-1 (Increlex®, Tercica, Inc., Brisbane, CA; n=8). LC mice were infused with vehicle (n=8). Mice were killed 28 days after injection, blood was collected by cardiac puncture and serum samples were stored at −80°C, and tumors were weighed and fixed in 10% normal buffered formalin for histological and immunohistochemical (IHC) analysis. IHC staining was performed on paraffin-embedded tissues using antibodies against Ki67 and cyclin D1 to assess proliferation. LID mice exhibited significantly smaller tumors (0.20 ± 0.02 g) than LC mice (0.45 ± 0.11 g, p&lt;0.05) or LID + IGF-1 mice (0.57 ± 0.14 g, p&lt;0.01). Serum IGF-1 levels were reduced approximately 60% in the LID mice relative to the LC mice (p&lt;0.01), while infusion of human IGF-1 resulted in total serum IGF-1 levels (murine plus human IGF-1) exceeding either LC or LID mice (p&lt;0.01). In contrast, insulin and leptin levels in LID mice were significantly higher than those seen in LC (p&lt;0.05) or LID+IGF-1 (p&lt;0.01) mice. Consistent with tumor burden data, LID tumors, relative to LC and LID + IGF-1, displayed less expression of proliferative markers. These findings suggest that genetic reduction of circulating IGF-1 levels decreases transplanted pancreatic tumor growth despite increased levels of insulin and leptin, underscoring the importance of the IGF-1 pathway as a pancreatic cancer prevention target. Citation Information: Cancer Prev Res 2010;3(1 Suppl):A102.