2013 SSAT PLENARY PRESENTATION Overexpressing TNF-Alpha in Pancreatic Ductal Adenocarcinoma Cells and Fibroblasts Modifies Cell Survival and Reduces Fatty Acid Synthesis via Downregulation of Sterol Regulatory Element Binding Protein-1 and Activation of Acetyl CoA Carboxylase Mazhar Al-Zoubi & Galina Chipitsyna & Shivam Saxena & Konrad Sarosiek & Ankit Gandhi & Christopher Y. Kang & Daniel Relles & Jocelyn AndrelSendecki & Terry Hyslop & Charles J. Yeo & Hwyda A. Arafat Received: 19 May 2013 /Accepted: 20 September 2013 /Published online: 4 October 2013 # 2013 The Society for Surgery of the Alimentary Tract Abstract The effect of tumor necrosis factor-alpha (TNF-α) gene delivery has been suggested as a potentially useful therapeutic approach to improve the chemotherapeutic treatment of patients with pancreatic ductal adenocarcinoma (PDA), but the exact mechanism of its action is not clearly understood. In this study, we analyzed the expression profile of TNF-α in PDA tissue and explored its potential role in fatty acid synthase (FAS) regulation in PDA cells and in fibroblasts. Quantitative real-time polymerase chain reaction was used to examine the expression of TNF-α in PDA, matching adjacent tissues, and benign lesions. Logistic regression models with robust variance were used to analyze the gene expression levels, and Kaplan–Meier survival curves were generated. In vitro, we overexpressed the TNF-α gene in PDA cells and fibroblasts and analyzed its effect on cell survival, migration, and on members of the FAS signaling pathway. We also evaluated TNF-α effects on a panel of inflammation-, angiogenesis-, and metastasis-related markers. In the tumor tissue of PDA patients, compared with their matched adjacent tissue, expression levels of TNF-α were not statistically different and did not correlate with survival or any other examined clinicopathological features. Overexpression of TNF-α significantly (p <0.05) reduced PDA and fibroblast cell migration. In PDA cells that highly overexpress TNF-α, this was associated with a significant reduction of FAS mRNA and protein expression levels and significant (p <0.05) reduction of SREBP-1 and ACC mRNA. Reduction of FAS by TNF-α was inhibited when either SREBP-1 or ACC was knocked down by siRNA. PDA cells and fibroblasts that overexpress TNF-α displayed differential regulation of several inflammation-related markers and reduced levels of metastasis-related genes. Our data demonstrate a previously unknown multi-targeted involvement of TNF-α in PDA lipogenesis and inflammation and metastasis and suggest that intratumoral introduction of TNF-α may have the potential as a novel therapeutic approach in human PDA. Keywords Pancreatic cancer . TNF-alpha . Fatty acid synthase . Inflammation Introduction Pancreatic ductal adenocarcinoma (PDA) remains the fourth leading cause of adult cancer mortality in the United States, and it is quite therapy-resistant. 1 At the time of diagnosis, most patients have advanced disease (either locally advanced or with distant metastases), and their median life expectancy is only 6 to 10 months. 2 Patients with locally advanced disease, Presented as a plenary presentation at the 54 th Annual Meeting of the Society for Surgery of the Alimentary Tract, 18–21 May 2013, Orlando, FL. M. Al-Zoubi : G. Chipitsyna : S. Saxena : K. Sarosiek : A. Gandhi : C. Y. Kang : D. Relles : C. J. Yeo : H. A. Arafat (*) Department of Surgery, The Jefferson Pancreatic, Biliary and Related Cancer Center, Thomas Jefferson University, 1015 Walnut Street, Suite 618 Curtis, Philadelphia, PA 19107, USA e-mail: harafat@une.edu J. AndrelSendecki : T. Hyslop Department of Biostatistics, The Jefferson Pancreatic, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA J Gastrointest Surg (2014) 18:257–268 DOI 10.1007/s11605-013-2370-7