title: Threonyl-tRNA synthetase overexpression correlates with angiogenic markers and progression of human ovarian cancer.
abstract: BACKGROUND
  Ovarian tumors create a dynamic microenvironment that promotes angiogenesis and reduces immune responses. Our research has revealed that threonyl-tRNA synthetase (TARS) has an extracellular angiogenic activity separate from its function in protein synthesis. The objective of this study was to test the hypothesis that TARS expression in clinical samples correlates with angiogenic markers and ovarian cancer progression.
  
  
  METHODS
  Protein and mRNA databases were explored to correlate TARS expression with ovarian cancer. Serial sections of paraffin embedded ovarian tissues from 70 patients diagnosed with epithelial ovarian cancer and 12 control patients were assessed for expression of TARS, vascular endothelial growth factor (VEGF) and PECAM using immunohistochemistry. TARS secretion from SK-OV-3 human ovarian cancer cells was measured. Serum samples from 31 tissue-matched patients were analyzed by ELISA for TARS, CA-125, and tumor necrosis factor-α (TNF-α).
  
  
  RESULTS
  There was a strong association between the tumor expression of TARS and advancing stage of epithelial ovarian cancer (p < 0.001). TARS expression and localization were also correlated with VEGF (p < 0.001). A significant proportion of samples included heavy TARS staining of infiltrating leukocytes which also correlated with stage (p = 0.017). TARS was secreted by ovarian cancer cells, and patient serum TARS was related to tumor TARS and angiogenic markers, but did not achieve significance with respect to stage. Multivariate Cox proportional hazard models revealed a surprising inverse relationship between TARS expression and mortality risk in late stage disease (p = 0.062).
  
  
  CONCLUSIONS
  TARS expression is increased in epithelial ovarian cancer and correlates with markers of angiogenic progression. These findings and the association of TARS with disease survival provide clinical validation that TARS is associated with angiogenesis in ovarian cancer. These results encourage further study of TARS as a regulator of the tumor microenvironment and possible target for diagnosis and/or treatment in ovarian cancer.
authors.forename: Theresa L
authors.initials: TL
authors.lastname: Wellman
authors.forename: Midori
authors.initials: M
authors.lastname: Eckenstein
authors.forename: Cheung
authors.initials: C
authors.lastname: Wong
authors.forename: Mercedes
authors.initials: M
authors.lastname: Rincon
authors.forename: Takamaru
authors.initials: T
authors.lastname: Ashikaga
authors.forename: Sharon L
authors.initials: SL
authors.lastname: Mount
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Francklyn
authors.affiliation: Departments of Pharmacology, University of Vermont, College of Medicine, Burlington, Vermont 05405, USA. karen.lounsbury@uvm.edu.
authors.forename: Karen M
authors.initials: KM
authors.lastname: Lounsbury
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism*; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D009375:Neoplasms, Glandular and Epithelial / Q000378:metabolism / Q000401:mortality / Q000473:pathology* / Q000503:physiopathology; D009389:Neovascularization, Pathologic; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology* / Q000503:physiopathology; D016019:Survival Analysis; D013914:Threonine-tRNA Ligase / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D059016:Tumor Microenvironment; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D014409:Tumor Necrosis Factor-alpha; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D013914:Threonine-tRNA Ligase