Abstract
Abstract Ovarian tumors create a dynamic microenvironment that promotes angiogenesis and reduces immune responses. There is growing evidence that tRNA synthetases have a role in cell signaling separate from their function in protein synthesis. Our research has revealed that threonyl-tRNA synthetase (TARS) has an extracellular angiogenic activity. Exploration of protein and mRNA databases further showed a connection between TARS expression and ovarian cancer. The objective of this study was to test the hypothesis that TARS is secreted by ovarian cancer cells and that its expression in clinical samples correlates with angiogenic markers and ovarian cancer progression. TARS secretion by SKOV3 human ovarian cancer cells was induced by hypoxia or tumor necrosis factor-α (TNF-α) as detected by ELISA and Western blot of culture media (p<0.001). For the clinical study, TARS, vascular endothelial growth factor (VEGF) and PECAM were assessed by immunohistochemistry in serial sections of paraffin embedded ovarian tissues from 70 patients diagnosed with epithelial ovarian cancer and 12 control patients. Serum samples from 31 tissue-matched patients were analyzed by ELISA for TARS, CA125, 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). 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). Together these results show that TARS is secreted in response to cell stress and that its expression is increased in epithelial ovarian cancer according to stage and 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. Citation Format: Theresa L. Wellman, Midori Eckenstein, Cheung Wong, Mercedes Rincon, Takamaru Ashikaga, Sharon L. Mount, Christopher S. Francklyn, Karen M. Lounsbury. Threonyl-tRNA synthetase overexpression correlates with angiogenesis and progression of human ovarian cancer [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-BIOL-1335.
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