Threonyl-tRNA synthetase overexpression correlates with angiogenic markers and progression of human ovarian cancer
1 Departments of Pharmacology, University of Vermont, College of Medicine, Burlington, Vermont 05405, USA
2 Departments of Obstetrics, Gynecology and Reproductive Sciences, Burlington, Vermont 05405, USA
3 Departments of Medicine, University of Vermont, College of Medicine, Burlington, Vermont 05405, USA
4 Medical Biostatistics, University of Vermont, College of Medicine, Burlington, Vermont 05405, USA
5 Departments of Pathology, University of Vermont, College of Medicine, Burlington, Vermont 05405, USA
6 Departments of Biochemistry, University of Vermont, College of Medicine, Burlington, Vermont 05405, USA
7 The Vermont Cancer Center, University of Vermont, College of Medicine, Burlington, Vermont 05405, USA
BMC Cancer 2014, 14:620 doi:10.1186/1471-2407-14-620Published: 27 August 2014
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.
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).
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).
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.