Abstract 2465: Microenvironmental sugars regulate pancreatic cancer stem cell transcription to promote an invasive phenotype

Abstract

Abstract Pancreatic cancer is a lethal disease and there are few effective therapies. Increased refined carbohydrate and specifically fructose consumption have been associated with increased pancreatic cancer risk in some studies. We recently demonstrated that fructose-treated pancreatic cancer cells grow in vitro at equivalent rates to glucose and observed that cancer cell metabolism of glucose and fructose are quite different whereby fructose increased nucleic acid synthesis, a feature of a highly aggressive cancer phenotype. A subset of cells within a tumor, termed cancer stem cells (CSC) that highly tumorigenic and resistant to chemotherapy. We recently demonstrated that the metabolism of fructose and glucose in pancreatic cancer is very different with fructose preferentially providing carbons for nucleic acid synthesis. To gain insight into how nutrients such as fructose might differentially regulate cancer cell metabolic pathways to promote an aggressive phenotype, we performed mRNA expression profiling followed by QT-PCR in fructose-treated pancreatic CSCs and compared gene expression to pancreatic CSCs maintained in normal medium. Following fructose-treatment (0.55-5.5mM), we demonstrated increased chemokine receptor4 (CXCR4), epidermal growth factor receptor (EGFR) and glutathione peroxidase (GPX1) mRNA expression in comparison to glucose- (0.55-5.5mM) or normal medium (22mM glucose) -treated pancreatic CSCs and in comparison to fructose- or glucose-treated pancreatic cancer non stem cells (NSC), whole Panc-1 cells and normal pancreatic ductal HPDE6 cells. In additional studies we observed that the nutrient sugar fructose selectively activates distinct tumorigenic signaling cascades in pancreatic CSCs including phosphorylated Akt and GSK-3α/β to increase CXCR4 to potentially promote growth, survival and metastases of pancreatic cancer stem cells. We also observed that fructose potently induced pancreatic CSC mRNA expression of the selective fructose transporter GLUT5, providing further insight into fructose-mediated actions in pancreatic CSCs. In summary, we demonstrate that sugars mediate effects beyond that of a simple substrate and that environmental dietary nutrients can alter gene expression to potentially modify the cancer phenotype. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2465. doi:10.1158/1538-7445.AM2011-2465