Background: Malignant pleural mesothelioma (MPM) is an aggressive and therapy-resistant tumor arising from pleural mesothelial cells. Recently, we have demonstrated that CD157, a GPI-anchored NADase/ADP-ribosyl cyclase regulating leukocyte diapedesis, is expressed by epithelial ovarian cancer and peritoneal mesothelial cells, controls tumor cell migration and peritoneal invasion and is a marker of poor prognosis. Because ovarian cancer and MPM share many similarities in terms of aggressiveness and progression, we hypothesized that CD157 could be involved in the control of the invasive behavior of MPM. To address the clinical and biological significance of CD157 in MPM, we investigated i) the expression of CD157 in tissue sections from surgical samples of MPM and its correlation to clinical-pathological features and outcome, and ii) its functional effects in both native and engineered mesothelioma cell lines. Materials and methods. CD157 expression was examined by immunohistochemistry in tissue sections from surgically resected MPM (n=81), quantified by histological score (H-score), categorized as at/above or below the median value of 60, and compared with clinical parameters. The functional role of CD157 was investigated by transfecting CD157 in MPM cell lines that have been used to study tumor cell migration, invasion, proliferation and chemoresistance with conventional in vitro cell-based assays. Results: CD157 proved to be expressed in 85% of MPM analyzed and CD157-H-score was associated with outcome on follow up in patients with biphasic MPM (P=0.034, n=43). Cox regression showed that CD157-H-score and membrane localization were independent prognostic factors of poor prognosis in biphasic MPM. Moreover, CD157 proved to be expressed in selected cell lines and its exogenous expression in the CD157-negative MSTO-211H biphasic MPM cell line significantly enhanced tumor cell motility and invasiveness through extracellular matrix proteins, increased tumor cell proliferation, and induced resistance to chemotherapy. Conclusions: These findings indicate that CD157 is expressed by the majority of MPM and its high level of expression and membrane localization are associated with shorter survival in patients with biphasic MPM. Moreover, CD157 is involved in the control of migratory and invasive behavior of biphasic MPM and might represent a novel biomarker with potential clinical utility.
CD157 is a novel prognostic marker of malignant pleural mesothelioma involved in the control of tumor aggressiveness
GIACOMINO, ALICE;MORONE, SIMONA;PARROTTA, ROSSELLA;LO BUONO, NICOLA;RAPA, IDA;RIGHI, Luisella;VOLANTE, Marco;RUFFINI, Enrico;ORTOLAN, Erika;FUNARO, Ada
2012-01-01
Abstract
Background: Malignant pleural mesothelioma (MPM) is an aggressive and therapy-resistant tumor arising from pleural mesothelial cells. Recently, we have demonstrated that CD157, a GPI-anchored NADase/ADP-ribosyl cyclase regulating leukocyte diapedesis, is expressed by epithelial ovarian cancer and peritoneal mesothelial cells, controls tumor cell migration and peritoneal invasion and is a marker of poor prognosis. Because ovarian cancer and MPM share many similarities in terms of aggressiveness and progression, we hypothesized that CD157 could be involved in the control of the invasive behavior of MPM. To address the clinical and biological significance of CD157 in MPM, we investigated i) the expression of CD157 in tissue sections from surgical samples of MPM and its correlation to clinical-pathological features and outcome, and ii) its functional effects in both native and engineered mesothelioma cell lines. Materials and methods. CD157 expression was examined by immunohistochemistry in tissue sections from surgically resected MPM (n=81), quantified by histological score (H-score), categorized as at/above or below the median value of 60, and compared with clinical parameters. The functional role of CD157 was investigated by transfecting CD157 in MPM cell lines that have been used to study tumor cell migration, invasion, proliferation and chemoresistance with conventional in vitro cell-based assays. Results: CD157 proved to be expressed in 85% of MPM analyzed and CD157-H-score was associated with outcome on follow up in patients with biphasic MPM (P=0.034, n=43). Cox regression showed that CD157-H-score and membrane localization were independent prognostic factors of poor prognosis in biphasic MPM. Moreover, CD157 proved to be expressed in selected cell lines and its exogenous expression in the CD157-negative MSTO-211H biphasic MPM cell line significantly enhanced tumor cell motility and invasiveness through extracellular matrix proteins, increased tumor cell proliferation, and induced resistance to chemotherapy. Conclusions: These findings indicate that CD157 is expressed by the majority of MPM and its high level of expression and membrane localization are associated with shorter survival in patients with biphasic MPM. Moreover, CD157 is involved in the control of migratory and invasive behavior of biphasic MPM and might represent a novel biomarker with potential clinical utility.
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