Abstract 299: Modulation of the leptin receptor in pancreatic cancer cells mediates tumor growth

Abstract

Abstract Background: Pancreatic cancer is the fourth leading cause of cancer death with a five year survival rate around 5%, which has not changed in 30 years. Obesity and increased abdominal adipose tissue independently correlate with an increased relative risk for the development of pancreatic cancer. These conditions have been associated with altered levels of adipokines, or adipose secreted cytokines. Circulating serum levels of the adipokine leptin are increasesddramatically in obese patients as well as in high fat diet induced obese mice. Leptin has been shown to induce oncogenic signaling in breast and prostate cancer. We have previously shown an increase in orthotopic pancreatic tumor size in high fat diet induced obese mice compared with regular diet control mice. We hypothesize that leptin signaling mediates pancreatic tumorigenesis. Methods: Leptin receptor status was determined in human as well as murine pancreatic cell lines. Leptin stimulated cell proliferation was determined using a modified BrdU assay. Leptin receptor levels were knocked down in human and murine pancreatic tumor cells using a shRNAmir approach. Leptin receptor shRNA Panc02 knockdown cells were injected orthotopically into the pancreas of C57/Bl6J mice on regular or high fat diet to determine the contribution of leptin to pancreatic tumor growth. Results: We have detected the long form of the leptin receptor in five human and four murine pancreatic cancer cell lines. In vitro administration of leptin stimulated proliferation of Panc1 and CFPAC1 cell lines, which was abrogated with co-incubation of a leptin antagonist. To better understand the mechanism of leptin-mediated signaling, we studied downstream targets and identified a significant increase in phosphorylation of STAT3 in Panc1, BXPC3 and CFPAC1 cell lines after leptin treatment. Orhtotopic injection of leptin receptor shRNA Panc02 cells into normal and obese mice showed a markedly diminished tumor growth in obese mice when compared to the nonsilencing control Panc02 cell growth in obese mice. Conclusion: These results implicate leptin as a mediator of pancreatic tumorigenesis and suggest that leptin activation is mediated in part through STAT3 signaling. Knockdown of the leptin receptor results in inhibition of high fat diet associated tumor growth in vivo. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 299. doi:1538-7445.AM2012-299