Syndecan-1 in Liver Diseases

Despite of the permanent progress in the understanding of mechanisms implicated in the development of liver diseases, the management of liver cirrhosis and malignant liver tumors are still a major medical challenge. The most important etiology factors of the primary liver diseases, including liver fibrosis and hepatocellular carcinomas (HCC), are hepatitis B and C viral infections (HBC, HCV) and alcohol consumption [1]. However, the liver is more frequently target of metastatic than primary tumors. These are mainly adenocarcinomas arisen from various tumors of the body, but the most common place of origin is colorectal cancer [2]. Tumors, developed in non-cirrhotic background can be treated by partial resection of the liver. As cirrhosis destroys the liver parenchyma, liver transplantation is the only effective therapeutic approach either without or with the presence of HCC. Here, in order to achieve the most effective organ allocation, objective scoring systems were necessary to develop. Recently, the most widely used system is the MELD (Model For End-Stage Liver Disease) score. MELD score is based on three entirely objective laboratory test, namely serum total bilirubin level, serum creatinine level and International Normalized Ratio (INR) [3].

In the meantime, liver injury is accompanied by deterioration of several other laboratory parameters. Among those we observed the changes of syndecan-1 (SDC1). This molecule, a member of the syndecan family, is the major proteoglycan of the liver, built up by and extracellular, a transmembrane and an intracellular domain. In proteoglycans glycosaminoglycans are covalently attached to the core protein. In case of syndecan-1 three heparan-sulphate and two chondroitin-sulphate side chains can be detected on the core protein. The extracellular domain of syndecan-1 interacts with numerous types of ligands, including growth factors, cytokines, receptors and enzymes [4]. Physiologically syndecan-1 is predominantly expressed on the surface of epithelial cells, but is also present on pre-B and plasma cells [5]. It has well-documented roles in wound repair, development, stem cell differentiation, inflammation and tumorigenesis [4, 6, 7]. Another characteristic of syndecan-1 is the shedding of the extracellular domain. SDC1 can be cleaved at the juxtamembrane site by various proteolytic enzymes, putting the extracellular domain in soluble form [6, 8]. The serum concentration of the shed extracellular domain increases in liver diseases such as non-alcoholic fatty liver disease and liver fibrosis, reported to be useful biomarker for disease monitoring [9, 10].

According to our previous studies the amount of heparan-sulphate and chondroitin-sulphate increases in various primary liver diseases, associated with altered expression of syndecan-1 [11, 12]. However, there is no indication in human diseases whether changes in syndecan-1 expression indicate protective or deleterious action?

Our aim was to correlate the amount of syndecan-1 in primary liver diseases and colorectal adenocarcinoma metastasis with relevant clinical data.

Syndecan is the major heparan-sulphate proteoglycan of the liver. Although its function in various physiological and pathological events is excessively studied we are far for understanding its role in liver diseases. This proteoglycan plays critical role in the clearance of lipoproteins from the circulation, acting as a VLDL receptor [14]. A typical feature of syndecan pathologies is the shedding of its extracellular domain, which subsequently appears in the circulation. Really several publications described elevated serum syndecan-1 level accompanying the deterioration of the liver [9]. This also implies, that assessment of liver syndecan as marker of the liver disease should calculate with the cell surface and shed syndecan-1 together.

Previously [11] and now in this present systematic study we demonstrated that the pathological events of the liver tissue is always related to the alteration of syndecan-1 expression. Recently we described, that increased expression of the proteoglycan triggers the synthesis of MMP-14, a protease playing critical role in matrix degradation, hindering this way the development of liver cirrhosis in experimental system [13].

Syndecan-1 as a transmembrane cell surface molecule is capable to initiate crosstalk between the extracellular and intracellular milieu, thus it is an important player of tissue communication, and co-receptor of cell surface TK receptors [15, 16]. Furthermore, it is involved in calcium signaling [17]. Now the question is, how can we translate the experimental data to the human liver diseases?

In this manuscript we focused on the changes of syndecan-1 developed in hepatocellular carcinoma with and without cirrhosis, as well as on its change as the response of tumor metastasis.

As we demonstrated the amount of syndecan-1 varies in primary and metastatic liver diseases compared to normal controls. In the different primary liver diseases like liver fibrosis or hepatocellular carcinoma we have found elevated syndecan-1 levels. The most prominent enhancement of syndecan-1 expression could be observed in cirrhosis based hepatocellular carcinoma and cirrhosis. Sorting out the factors responsible for this upregulation HCV turned out to be responsible for it. Really, it was published, that syndecan-1 is the receptor of HCV and other viruses as well [18]. In the meantime this over production of syndecan-1 goes together with its increased shedding, which seemed to be beneficiary in experimental liver fibrosis.

Our experimental data indicated, that syndecan-1 overexpression inhibits the early stages of liver fibrogenesis through its shedding. The shedded extracellular domain of syndecan-1 binds and eliminates TGFβ1, one of the most important cytokines in fibrogenesis, to the circulatory system [13]. In this study both syndecan-1 and TGFβ1 concentration proved to be elevated in the sera in accordance with previous publications demonstrating that syndecan-1 increased in the patients’ sera parallel with the severity of the disease [9, 10].

For liver diseases like liver fibrosis still only transplantation is the curative solutions. In order to establish the best organ allocation objective decision making is necessary. In the decision making process MELD score is a helpful tool to establish the severity of the disease and predicts 3-month mortality among patients with chronic liver disease waiting for transplantation [19]. In in vivo experiment syndecan-1 attenuated acetaminophen induced acute liver failure and promoted liver repair in mice [20]. In our study enhanced MELD score groups went together with higher amount of syndecan-1 on hepatocyte surface. These data suggests that although syndecan-1 has a protective role in liver fibrosis and liver failure, this defense mechanism can exhaust after a while.

Compared to normal liver areas increased amount of syndecan-1 could be observed both in cirrhosis and non-cirrhosis based hepatocellular carcinoma, however it is much higher in the former, where syndecan-1 expression is also high in the peritumoral cirrhotic areas. Our results showing increased syndecan-1 expression in HCV infected specimens were full agreement with the previous studies describing that syndecan-1 and its heparan-sulphate glycosaminoglycan chain is a major receptor for HCV internalization to hepatocytes [18, 21].

Previous studies have already proved that syndecan-1 expression is down regulated in case of colon adenocarcinomas compared to normal colon epithelium, and this has a strong association with the size of the tumorous tissue [22]. In our studies we have also observed the same decrease in case of colon samples, and similarly low amount of it was observed in their liver metastases either synchron or metachron cases. If we compared the non tumorous surrounding liver samples to normal liver higher amount of syndecan-1 can be observed. It is a question to address if in this scenario the elevated syndecan-1 level is part of the defensive mechanism or the tumorous niche?