Abstract 926: Nitric oxide enhances tumor progression and disease aggressiveness in pancreatic cancer

Abstract

Abstract Pancreatic Ductal Adenocarcinoma (PDAC) is among the most malignant cancer, with 5-year survival of a mere 6%. Chronic inflammation is associated with an increased risk of PDAC. Nitric oxide (NO•) is an important mediator of immune and inflammatory responses and plays a role in tumorigenesis. The principal source of an increased and sustained level of NO• is inducible nitric oxide synthase (NOS2). In this study, we have tested the hypothesis that NO• enhances tumor progression in pancreatic cancer. We found that a higher NOS2 expression in tumors was associated with poor survival in resected PDAC patients (p=0.011). We then used a genetic strategy to investigate the role of NO• in the development and progression of PDAC by deleting NOS2 gene in a genetically engineered mouse model of pancreatic cancer (KPC mice) with pancreas specific activation of mutant KRAS and P53, which faithfully recapitulates the development and progression of human pancreatic cancer. NOS2-deficient KPC mice showed a longer survival as compared to the KPC littermates with wild type NOS2 (p<0.01). Tumors from KPC/NOS2-/- mice showed reduced tumor cell proliferation and increased apoptosis as indicated by a lower expression of Ki67 and a higher level of activated caspase-3, as compared with KPC mice. Furthermore, tumors from KPC/NOS2-/- mice were less vascularized as compared with KPC mice, as indicated by CD31 expression. Additionally, NOS2-deficiency led to a decreased inflammatory response by attenuation of macrophage recruitment in pancreatic tumors as indicated by a significantly lower expression of F4/80. However, in contrast FOXP3+ regulatory T-cells were increased in tumors from KPC/NOS2-/- mice. Further mechanistic analysis revealed a higher expression of ph-FOXO3 and nuclear ph-ERK in tumors from KPC mice as compared with KPC/NOS2-/- mice. Analysis of human PDAC samples showed a positive correlation between NOS2 and ph-FOXO3 expression (P=0.004). In summary, NOS2 gene expression in tumors is a candidate prognostic marker in resected pancreatic cancer patients, and NOS2/NO• signaling may contribute to the pancreatic tumor progression by inactivating FOXO3 in KPC mice. In this ongoing study, we are further investigating the mechanistic role of NO• in disease progression. Citation Format: Jian Wang, Peijun He, Matthias M. Gaida, Shouhui Yang, Aaron Schetter, Jochen Gaedcke, Michael Ghadimi, Thomas Ried, Harris G. Yfantis, Dong H. Lee, Jonathan M. Weiss, Jim Stauffer, Nader Hanna, H. Richard Alexander, S. Perwez Hussain. Nitric oxide enhances tumor progression and disease aggressiveness in pancreatic cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 926. doi:10.1158/1538-7445.AM2014-926