1. Background Malignant pleural mesothelioma (MM) is an asbestos-related tumor with poor prognosis, difficult to diagnose and treat effectively. Understanding the mechanisms of MM development and invasiveness, and identifying potential biomarkers are intrinsic to the prevention, screening and effective therapies. Recently, we have demonstrated that CD157, a glycosylphosphatidylinositol-anchored NADase/ADP-ribosyl cyclase-related molecule regulating leukocyte diapedesis, plays a pivotal role in the control of ovarian cancer cell migration and peritoneal invasion and represents a marker of poor prognosis in serous ovarian cancer. Here we investigated the clinical and biological significance of CD157 in MM analyzing i) the expression of CD157 in tissue sections from surgical samples of MM in correlation to clinical-pathological features and outcome and ii) its biological effects in both native and engineered mesothelioma cell lines. 2. Methods CD157 expression was examined by immunohistochemistry in tissue sections from surgically resected MM (n = 81), quantified by histological score (H-score), categorized as at/above or below the median value of 60, and compared with clinical parameters. Native and engineered MM cell lines were analysed for CD157 expression using flow cytometry, Western blot and RT-PCR. Cell proliferative activity, tumor cell migration and invasion were studied using conventional in vitro cell-based assays. Soluble CD157 in serum and pleural effusion was detected by means of a novel enzyme-linked immunosorbent assay. 3. Results Immunohistochemical analysis revealed that CD157 is expressed in 85% (69/81) of the specimens analyzed at varying levels and with discrete localization patterns. CD157 H-score did not associate with patient age at surgery, sex, histological type, IMIG disease stage, or asbestos exposure, whereas, it was statistically associated with outcome on follow up in patients with biphasic MM (P = 0.034, n=43). Univariate analysis of patients with biphasic MM demonstrated that patients with CD157-H-score ≥60 and those with CD157 immunostaining localized at the cell membrane had significantly shorter survival then patients with CD157-H-score <60 (log-rank test: P = 0.037) or with cytoplasmic staining (log-rank test: P = 0.038), respectively. Multivariable Cox regression showed that CD157 H-score and membrane localization were powerful independent prognostic factors of poor prognosis in biphasic MM. In vitro studies highlighted that CD157 is expressed in selected cell lines; moreover, forced expression of CD157 in the CD157-negative MSTO-211H biphasic MM cell line i) significantly increased the rate of tumor cell proliferation, ii) enhanced cell motility and, iii) increased the ability of tumor cells to invade the extracellular matrix . Preliminary results indicated that CD157 is released in the serum and in the pleural effusion of patients with mesothelioma. The evaluation of soluble CD157 potential clinical significance and/or prognostic utility deserves further investigation. 4. Conclusions These findings indicate that CD157 could represent a novel biomarker in MM since it is expressed by the majority of MM tissues and its expression level and localization are associated with shorter survival in patients with biphasic MM. Moreover, CD157 expression promotes proliferation and motility and increases the invasive potential of MM cells.
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