**1. Introduction**

Malignant pleural mesothelioma (MPM) is an aggressive tumor of mesothelial origin that occurs after a long latency period following asbestos exposure often comprising several decades [1–4]. This tumor occurs mostly in the pleura (>75%) and less often in the peritoneum (10–20%) or pericardium (1%) [5,6]. The median survival time of malignant pleural mesothelioma is less than 12 months [7]. This survival is strongly influenced by subtype of the tumor and time of diagnosis [3,8]. The diagnosis of MPM is challenging, which often leads to a late diagnosis and together with tumor aggressiveness results in a poor prognosis. Diagnosis is based on testing of multiple immunohistochemical (IHC)

markers of biopsies or cytological samples, and soluble biomarker analysis of pleural effusion to distinguish MPM from other lung malignancies [9]. The optimal treatment is surgery in combination with chemotherapy and radiotherapy, or both [10]. Most patients present with a pleural effusion as first symptom and cytological diagnosis increases the chance for earlier diagnosis and prolongs patient survival [11]. Among soluble biomarkers hyaluronan and mesothelin are the best characterized biomarkers for diagnosis of MPM.

Hyaluronan (HA), a negatively charged glycosaminoglycan of the extracellular matrix (ECM), consists of the repeating disaccharide units (glucuronic acid and *N*-acetylglucosamine), is an established biomarker used in diagnosis of MPM [12–14]. Hyaluronan is involved in different functions such as cell growth, angiogenesis, differentiation, cell migration, wound healing and the regulation of plasma protein distribution [13,15]. Hyaluronan is a well-known biomarker for MPM [14,16–18].

Mesothelin is a 40-KD cell membrane glycoprotein, which presents on normal mesothelial cells and is highly expressed in different human cancers of the lung, endometrium, stomach and pancreas [19]. Mesothelin is synthesized as a 72-KD protein anchored in the cell membrane. It sheds a 32-KD fragment called *N*-ERC/mesothelin, leaving a 40-KD fragment named C-ERC/mesothelin. Both fragments can be detected in the effusion supernatant [20]. The role of mesothelin in the development of normal cells is not known, whereas, in cancer cells, mesothelin promotes tumor progression by interacting with other membrane proteins, such as CA125 [21–23]. In recent years, Mesothelin has received considerable attention for immune-based therapies and as a promising biomarker, because of its low expression level in normal cells [24,25].

Syndecan-1 (SDC-1) is a transmembrane heparan sulfate proteoglycan containing glycosaminoglycan (GAG) side chains linked to *N*-terminal extracellular domain of the core protein. Syndecan-1 acts as a co-receptor for many regulatory proteins, such as growth factors, cytokines and integrins through its GAG, mainly heparan sulfate, chains. This interaction leads to regulation of different cellular processes including proliferation, migration, differentiation and angiogenesis by alteration of different signaling pathways [26,27]. In different cancer types syndecan-1 plays dynamic roles, whereby it can either suppress or promote tumor progression [28–31].

The aim of this study is to evaluate shed SDC-1 in pleural effusions together with angiogenesis related proteins and identify optimal biomarker batteries that allow earlier diagnosis and improve the possibilities to distinguish MPM from metastatic adenocarcinoma and reactive conditions.
