Abstract
BackgroundOvarian 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.MethodsProtein 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).ResultsThere 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).ConclusionsTARS 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.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2407-14-620) contains supplementary material, which is available to authorized users.
Highlights
Ovarian tumors create a dynamic microenvironment that promotes angiogenesis and reduces immune responses
In tissue arrays displayed in the Human Protein Atlas, Threonyl-tRNA synthetase (TARS) protein is moderately expressed in normal tissues but is highly expressed in ovarian tumors (9 of 12) [15]
Analysis of a Gene Expression Omnibus (GEO) Profile dataset of ovarian cancer samples revealed that TARS mRNA levels are significantly upregulated in ovarian carcinoma and reduced in patients treated with neoadjuvant carboplatin/paclitaxel chemotherapy (Figure 1, see Additional file 2) (GEO accession GDS2785; published by Moreno et al [18])
Summary
Ovarian tumors create a dynamic microenvironment that promotes angiogenesis and reduces immune responses. The canonical function of TARS is to charge threonine onto tRNA during protein synthesis, it has been identified as an auto-antibody (PL-7) target in myositis autoimmune disorders [10] The etiology of these diseases includes TNF-α signaling, and there is an epidemiological linkage between myositis and several different cancers [11,12]. We recently discovered that TARS has direct extracellular angiogenic activity both in vitro and in vivo through a mechanism that includes attraction of endothelial cells [13] These lines of evidence led to the hypothesis that TARS plays a role in the tumor microenvironment and may be an indicator of progression in angiogenic and/or inflammatory cancers
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