Abstract 4117: Increased pancreatic adipocyte hypertrophy in EL-Kras/PEDF null mice with versus without pancreatic cancer

Abstract

Abstract Understanding non-parenchymal contributions to disease etiology and factors that assess risk and prognosis are currently key points of interest in pancreatic cancer research. One such focus is in regards to fat, where obesity and increased visceral fat enhance risk and predict worse prognosis for pancreatic cancer patients. Pigment epithelium-derived factor (PEDF), initially identified for its potent anti-angiogenic activity, has been recently implicated in metabolism and adipogenesis, and loss of PEDF in mice promotes pancreatic hyperplasia and visceral obesity. In an attempt to create a model of pancreatic cancer that emulates metabolic features related to fat content, we generated PEDF knockout mice with KrasG12D-induced pancreatic neoplasia, where oncogenic Kras can also induce adipogenesis (typically observed as lipoatrophy). We have recently shown that EL-KrasG12D/PEDF null mice developed invasive pancreatic cancer associated with increased peripancreatic fat with adipocyte hypertrophy and pancreatic steatosis. Indeed, the stroma within the pancreas of these mice demonstrated higher levels of tail interacting protein 47 (TIP47, Perilipin 3) and adipose differentiation-related protein (ADRP, Perilipin 2), two lipid droplet associated proteins. In this study, we expanded upon this work to demonstrate that in most EL-Kras/PEDF null mice, there appeared to be greater number of neoplastic lesions near neighboring fat stores. In addition, there was a significant increase in the size of adipocytes (greater adipocyte hypertrophy) in EL-Kras/PEDF null mice with invasive cancer as opposed to age-matched mice with an identical genotype without the presence of cancer. Despite increased adipocytes in mice with cancer, there was no significant difference in overall body weight between these cohorts of animals. Future work aims at identifying if neoplastic lesions near adipocytes have a greater proliferative index and hence an increase in size. Ultimately, we hope to demonstrate that larger and more numerous adipocytes contribute to the development of pancreatic cancer. These data highlight the importance of lipid metabolism in the tumor microenvironment and identify PEDF as a critical negative regulator of both adiposity and tumor invasion in the pancreas, with implications that PEDF's effect on fat stores may induce cellular events leading to invasive disease. 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 4117. doi:1538-7445.AM2012-4117