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Nitric oxide enhances tumor progression and disease aggressiveness in pancreatic cancer

Thursday, September 17, 2015 — Poster Session II

12:00 p.m. – 1:30 p.m.
FAES Terrace


  • J Wang
  • P He
  • MM Gaida
  • S Yang
  • A Schetter
  • J Gaedcke
  • BM Ghadimi
  • T Ried
  • HG Yfantis
  • DH Lee
  • JM Weiss
  • J Stauffer
  • N Hanna
  • HR Alexander
  • SP Hussain


Pancreatic Ductal Adenocarcinoma (PDAC) is among the most malignant cancers, with 5-year survival of 6%. Chronic inflammation is associated with increased risk of PDAC. Nitric oxide (NO) is an important mediator of 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). We found that higher NOS2 expression in tumors was associated with poor survival in resected PDAC patients. We then investigated the role of NO by deleting NOS2 gene in a genetically engineered mouse model of pancreatic cancer (KPC mice) with pancreas-specific activation of mutant KRAS and P53. As a result, genetic NOS2 depletion from KPC mouse model has increase the survival of KPC mice. Tumors from NOS2-deficient mice (NKPC) were less vascularized and relatively well differentiated compared to the poorly differentiated KPC tumors. NKPC tumors exhibit less inflammatory response, including with less tumor infiltrating macrophages, less Ccl2 expression and decreased miR-21 expression. Primary tumors cells from NKPC mice showed deceased proliferation rate and decreased metastatic potential. In addition, NOS2 deficiency resulted in more apoptotic cell death in KPC tumors. Further investigation showed that NOS2 depletion has reversed the phosphorylation and inactivation of tumor suppressor FOXO3, through inhibiting the MEK/ERK signaling. A positive correlation of NOS2 and pFOXO3 has also been found in human PDAC specimen. In conclusion, NOS2/NO signaling contributed to pancreatic cancer progression and the inhibition of NOS2/NO signaling may serve as a potential therapeutic strategy for human PDAC.

Category: Cancer Biology