CD157 enhances malignant pleural mesothelioma aggressiveness and predicts poor clinical outcome.

Erika Ortolan,Ida Rapa,Enrico Ruffini,Marco Volante,Francesca Martinetto,Enza Ferrero,Silvia Novello,Ada Funaro,Sara Orecchia,Giorgio Scagliotti,Luisella Righi,Alice Giacomino,Simona Morone,Nicola Lo Buono

doi:10.18632/oncotarget.2186

Abstract

Malignant mesothelioma is a deadly tumor whose diagnosis and treatment remain very challenging. There is an urgent need to advance our understanding of mesothelioma biology and to identify new molecular markers for improving management of patients. CD157 is a membrane glycoprotein linked to ovarian cancer progression and mesenchymal differentiation. The common embryonic origin of ovarian epithelial cells and mesothelial cells and the evident similarities between ovarian and mesothelial cancer prompted us to investigate the biological role and clinical significance of CD157 in malignant pleural mesothelioma (MPM). CD157 mRNA and protein were detected in four of nine MPM cell lines of diverse histotype and in 85.2% of MPM surgical tissue samples (32/37 epithelioid; 37/44 biphasic). CD157 expression correlated with clinical aggressiveness in biphasic MPM. Indeed, high CD157 was a negative prognostic factor and an independent predictor of poor survival for patients with biphasic MPM by multivariate survival analysis (HR = 2.433, 95% CI 1.120-5.284; p = 0.025). In mesothelioma cell lines, CD157 gain (in CD157-negative cells) or knockdown (in CD157-positive cells) affected cell growth, migration, invasion and tumorigenicity, most notably in biphasic MPM cell lines. In these cells, CD157 expression was associated with increased activation of the mTOR signaling pathway, resulting in decreased platinum sensitivity. Moreover, a trend towards reduced survival was observed in patients with biphasic MPM receiving postoperative platinum-based chemotherapy. These findings indicate that CD157 is implicated in multiple aspects of MPM progression and suggest that CD157 expression could be used to stratify patients into different prognostic groups or to select patients that might benefit from particular chemotherapeutic approach.

Highlights

Malignant mesothelioma is a rare but highly aggressive tumor arising from the mesothelial cells lining the pleural, peritoneal and pericardial cavities
We demonstrated that CD157 is expressed in epithelial ovarian cancer where it contributes to tumor progression by promoting mesenchymal differentiation [10] and is an independent prognostic factor of reduced survival [11]
On the same panel of Malignant pleural mesothelioma (MPM) cell lines we investigated the expression of CD38, the other member of the NADase/ADP-ribosyl cyclase gene family

Summary

Introduction

Malignant mesothelioma is a rare but highly aggressive tumor arising from the mesothelial cells lining the pleural, peritoneal and pericardial cavities. Exposure to asbestos is the major risk factor [1] a latency period often exceeding four decades may pass from first exposure to disease onset [2]. Malignant pleural mesothelioma (MPM) is by far the most common form of this disease, and a vast majority of patients are diagnosed in advanced stages. MPM mainly consists of three distinct subtypes: epithelioid, sarcomatoid and biphasic. The epithelioid subtype is the most common, accounting for 50-60% of MPM: it is characterized by a papillary or pseudo-glandular growth pattern and has the best prognosis. The sarcomatoid subtype is the rarest form: it is characterized by a diffuse sarcomatous morphology and has the worst prognosis. The biphasic subtype accounts for 20-35% of MPM: these tumors contain both epithelial and mesenchymal components that merge into one another, likely representing an intermediate differentiation step in the epithelial-to-mesenchymal transition (EMT) process [4, 5]

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Results

Conclusion