Abstract
Stress-induced phosphoprotein 1 (STIP1) has been recently identified as a released biomarker in human ovarian cancer. In addition, STIP1 secreted by human ovarian cancer cells has been shown to promote tumor cell proliferation by binding to ALK2 (activin A receptor, type II-like kinase 2) and activating the SMAD-ID3 signaling pathways. In this study, a total of 330 ovarian cancer tumor samples were evaluated for STIP1 expression by immunohistochemistry and analyzed for a possible correlation with patient characteristics and survival. The quantification of immunoreactivity was accomplished by applying an immunohistochemical scoring system (histoscore). Patients with high-level STIP1 expression (histoscore ≥169) had a significantly worse survival (high STIP1, mean survival time = 76 months; low STIP1, mean survival time = 112 months; P<0.0001). Moreover, STIP1 histoscores were significantly higher in high-grade tumors (grade 3) than in low-grade (grade 1–2) malignancies (P<0.0001), suggesting that STIP1 may be a proxy for tumor aggressiveness. The results of multivariable analysis revealed that high STIP1 histoscores, advanced stages, histologic types, and the presence of residual disease (≥2 cm) were independent predictors of poor prognosis. The addition of STIP1 histoscores improved the prediction of overall and progression-free survival rates in the multivariable Cox proportional hazard model. The treatment of ovarian cancer cells with recombinant STIP1 stimulated cell proliferation and migration, but co-treatment with anti-STIP1 antibodies abrogated this effect. Our findings suggest that STIP1 expression may be related to prognosis and that the STIP1 pathway may represent a novel therapeutic target for human ovarian cancer.
Highlights
Epithelial ovarian cancer is one of the most lethal malignancies affecting women [1]
For the identical anti-Stress-induced phosphoprotein 1 (STIP1) antibody used in IHC throughout this study, western blot analysis of multiple ovarian cancer cell lines confirmed its specificity in recognizing STIP1 (Figure S1)
Higher STIP1 histoscores were significantly associated with older age ($50 years), advanced stage, the presence of non-mucinous cancers, grade 3, invasive cancer, higher cancer antigen 125 (CA125) levels ($35 U/mL), and suboptimal primary surgical cytoreduction (Table 1)
Summary
Epithelial ovarian cancer is one of the most lethal malignancies affecting women [1]. 225,500 ovarian cancer new cases are occurring worldwide each year, responsible for 140,200 deaths [2]. The measurement of serum cancer antigen 125 (CA125) levels has become standard practice for the preoperative evaluation of ovarian masses [4]. CA125 has been shown to be useful for monitoring therapeutic response and in the surveillance of patients with epithelial ovarian cancer [5]. Due to the limitations of CA125 as a disease marker, there is an urgent need for new biomarkers that can be used as prognostic indicators in ovarian cancer to effectively differentiate between aggressive and less aggressive disease
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