title: Loss of SOD3 (EcSOD) Expression Promotes an Aggressive Phenotype in Human Pancreatic Ductal Adenocarcinoma.
abstract: OBJECTIVE
  Pancreatic ductal adenocarcinoma (PDA) cells are known to produce excessive amounts of reactive oxygen species (ROS), particularly superoxide, which may contribute to the aggressive and refractory nature of this disease. Extracellular superoxide dismutase (EcSOD) is an antioxidant enzyme that catalyzes the dismutation of superoxide in the extracellular environment. This study tests the hypothesis that EcSOD modulates PDA growth and invasion by modifying the redox balance in PDA.
  
  
  METHODS
  We evaluated the prognostic significance of EcSOD in a human tissue microarray (TMA) of patients with PDA. EcSOD overexpression was performed in PDA cell lines and animal models of disease. The impact of EcSOD on PDA cell lines was evaluated with Matrigel invasion in combination with a superoxide-specific SOD mimic and a nitric oxide synthase (NOS) inhibitor to determine the mechanism of action of EcSOD in PDA.
  
  
  RESULTS
  Loss of EcSOD expression is a common event in PDA, which correlated with worse disease biology. Overexpression of EcSOD in PDA cell lines resulted in decreased invasiveness that appeared to be related to reactions of superoxide with nitric oxide. Pancreatic cancer xenografts overexpressing EcSOD also demonstrated slower growth and peritoneal metastasis. Overexpression of EcSOD or treatment with a superoxide-specific SOD mimic caused significant decreases in PDA cell invasive capacity.
  
  
  CONCLUSIONS
  These results support the hypothesis that loss of EcSOD leads to increased reactions of superoxide with nitric oxide, which contributes to the invasive phenotype. These results allow for the speculation that superoxide dismutase mimetics might inhibit PDA progression in human clinical disease.
authors: Department of Surgery, University of Iowa, Iowa City, Iowa.
authors: Brianne R
authors: BR
authors: O'Leary
authors: Department of Radiation Oncology, University of Iowa, Iowa City, Iowa.
authors: Melissa A
authors: MA
authors: Fath
authors: Department of Pathology, University of Iowa, Iowa City, Iowa.
authors: Andrew M
authors: AM
authors: Bellizzi
authors: Department of Surgery, University of Iowa, Iowa City, Iowa.
authors: Jennifer E
authors: JE
authors: Hrabe
authors: Department of Biostatistics, University of Iowa, Iowa City, Iowa.
authors: Anna M
authors: AM
authors: Button
authors: Department of Radiation Oncology, University of Iowa, Iowa City, Iowa.
authors: Bryan G
authors: BG
authors: Allen
authors: Department of Radiation Oncology, University of Iowa, Iowa City, Iowa.
authors: Adam J
authors: AJ
authors: Case
authors: National Cancer Institute, Bethesda, Maryland.
authors: Sean
authors: S
authors: Altekruse
authors: Department of Radiation Oncology, University of Iowa, Iowa City, Iowa.
authors: Brett A
authors: BA
authors: Wagner
authors: Department of Radiation Oncology, University of Iowa, Iowa City, Iowa.
authors: Garry R
authors: GR
authors: Buettner
authors: Department of Epidemiology, University of Iowa, Iowa City, Iowa.
authors: Charles F
authors: CF
authors: Lynch
authors: University of Hawaii Cancer Center, Honolulu, Hawaii.
authors: Brenda Y
authors: BY
authors: Hernandez
authors: University of Southern California, Los Angeles, California.
authors: Wendy
authors: W
authors: Cozen
authors: Galera Therapeutics, Malvern, Pennsylvania.
authors: Robert A
authors: RA
authors: Beardsley
authors: Galera Therapeutics, Malvern, Pennsylvania.
authors: Jeffery
authors: J
authors: Keene
authors: Department of Microbiology, University of Iowa, Iowa City, Iowa.
authors: Michael D
authors: MD
authors: Henry
authors: Department of Radiation Oncology, University of Iowa, Iowa City, Iowa.
authors: Frederick E
authors: FE
authors: Domann
authors: Department of Radiation Oncology, University of Iowa, Iowa City, Iowa.
authors: Douglas R
authors: DR
authors: Spitz
authors: Department of Surgery, University of Iowa, Iowa City, Iowa. Department of Radiation Oncology, University of Iowa, Iowa City, Iowa. james-mezhir@uiowa.edu.
authors: James J
authors: JJ
authors: Mezhir
mesh_terms: D000818:Animals; D015153:Blotting, Western; D021441:Carcinoma, Pancreatic Ductal / Q000473:pathology*; D064593:Heterografts; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D009361:Neoplasm Invasiveness / Q000473:pathology*; D010190:Pancreatic Neoplasms / Q000473:pathology*; D010641:Phenotype; D017382:Reactive Oxygen Species; D060888:Real-Time Polymerase Chain Reaction; D018426:SEER Program; D013482:Superoxide Dismutase / Q000096:biosynthesis* / Q000378:metabolism; D046888:Tissue Array Analysis
chemical_list: D017382:Reactive Oxygen Species; C441642:SOD3 protein, human; D013482:Superoxide Dismutase
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