Elsevier

Hepatology Research

Volume 34, Issue 1, January 2006, Pages 50-56
Hepatology Research

Expression of epithelial cellular adhesion molecule (Ep-CAM) in chronic (necro-)inflammatory liver diseases and hepatocellular carcinoma

https://doi.org/10.1016/j.hepres.2005.10.006Get rights and content

Abstract

Epithelial cell adhesion molecule (Ep-CAM) is expressed in a several epithelial tissues and carcinomas, but not on mature hepatocytes. Here, we analysed the expression of Ep-CAM in 230 patients suffering from various liver diseases like chronic hepatitis B and C (HBV and HCV infection), chronic autoimmune hepatitis (AIH), chronic alcoholic liver disease (ALD), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), hereditary hemochromatosis and dysplastic nodules (DNs) as well as hepatocellular carcinomas (HCCs) and cholangiocellular carcinomas (CCCs) by immunohistochemistry. De novo hepatocellular Ep-CAM expression was found in 75.9% of ALD (22/29), 63.6% of HCV (21/33) and 55.6% of each AIH and HBV cases (5/9 and 15/27, respectively). Lower Ep-CAM expression levels were observed for primary sclerosing liver diseases (PBC and PSC) with 25% (3/12) and 7.7% (1/13) of cases. Moreover, only 14.3% of HCCs (9/63) manifested expression, while all CCCs showed strong Ep-CAM expression (5/5). For DNs and hereditary hemochromatosis, Ep-CAM expression was found in 10 and 50% (3/30 and 2/4), respectively. In HBV and HCV, Ep-CAM expression correlated significantly with inflammatory activity as assessed by histological parameters and to the extent of fibrosis. In addition, for HCV also transaminase levels correlated significantly with Ep-CAM expression. Our results indicate that de novo Ep-CAM expression in hepatocytes is frequent in inflammatory liver diseases and is potentially linked to regenerative activity. CCCs and Ep-CAM positive HCCs may represent an attractive target group for Ep-CAM-directed immunotherapies, yet unwanted toxicity may limit the use of such strategies due to Ep-CAM expression in biliary epithelium and several chronic liver diseases such as HBV-and HCV-hepatitis.

Introduction

Ep-CAM, also known as EGP34, EGP-2, HEA125, GA733-2, ESA, KSA, KS1-4, MK-1 and 17-1A antigen, is a 40 kDa human epithelia-specific glycoprotein, which is encoded by the GA733-2 gene [1], [2]. It functions as an epithelial cell adhesion molecule mediating Ca2+-independent homotypic cell-to-cell adhesion. Ep-CAM is expressed in a wide variety of normal epithelial tissues and is frequently over-expressed in most human adenocarcinomas, but also in squamous cell carcinomas [3]. While proliferating embryonic hepatocytes and all hepatocellular stem cells (e.g. in “ductular proliferations”) were reported to express Ep-CAM, mature hepatocytes from adult tissue, which are interconnected by E-cadherin, were found to be negative for Ep-CAM expression [4]. Two studies analysing a limited number of patient samples indicated that Ep-CAM is also de novo expressed on hepatocytes of tissues from chronic liver diseases and in so-called ‘ductular proliferation’-regenerating hepatocellular stem cells, which express Ep-CAM at all maturation stages until reaching the terminal differentiation stage of mature hepatocytes, which are Ep-CAM negative [4], [5].

With respect to cancer, the role of Ep-CAM in tumorigenesis of breast cancer cells has recently been investigated using small inhibitory RNA molecules (siRNA) [6]. This study has shown that proliferation, invasiveness and migration of breast cancer cells was significantly reduced if Ep-CAM over-expression was selectively reduced by siRNA. These roles of Ep-CAM may be explained by an antagonistic function of Ep-CAM with another cell adhesion molecule of epithelia (e.g. E-cadherin), which co-localizes with Ep-CAM along the lateral surface of epithelial cells [7]. Loss of membranous E-cadherin expression is associated with poor differentiation, increased invasiveness and metastatic potential of tumors [8]. Due to its frequent over-expression in various types of cancer, Ep-CAM has been selected as a target for numerous antibody-based cancer therapies [9]. These include monoclonal and bi/trispecific antibodies, vaccination strategies and toxin-conjugated antibody fragments. Here, we have systematically analysed a large number of tissues from patients with chronic inflammatory and neoplastic liver diseases and investigated a possible correlation of Ep-CAM expression with the level of fiber content and (necro-)inflammation.

Section snippets

Patients and tissues

Two-hundred and thirty different liver tissue specimens were characterised by immunohistology for Ep-CAM and for relevant morphological parameters as outlined below. Ninety eight liver neoplasias (63 hepatocellular carcinomas (HCCs), five cholangiocellular carcinomas (CCCs) and 30 dysplastic nodules (DNs)) as well as five normal liver specimens were analysed. Among the 127 biopsies from non-neoplastic diseases, 33 were from patients with chronic hepatitis C (HCV), 27 from patients with chronic

Ep-CAM expression in normal liver tissue

Immunohistochemical staining of normal liver tissue with a human Ep-CAM-specific murine monoclonal antibody showed strong staining of all bile duct epithelia, while hepatocytes showed no detectable staining (Fig. 1(A)). We also noted that in diseased liver ductular proliferations and single small cells, likely to represent proliferating precursor cells for ductules and hepatocytes, were positive for Ep-CAM (data not shown).

Ep-CAM expression in neoplastic liver lesions

Dysplastic nodules showed Ep-CAM expression in only three out of 30

Discussion

This study investigated hepatic expression of Ep-CAM under various defined pathological conditions. Whereas no Ep-CAM expression was observed in normal mature hepatocytes, most (necro-)inflammatory diseases and CCCs showed notable Ep-CAM staining. Lower intensity and frequency or no hepatocellular Ep-CAM expression at all was observed in chronic biliary diseases such as PSC and PBC and in the majority of HCCs. Although Ep-CAM neoexpression was not specific for the etiology of liver diseases, it

References (19)

  • P.T. Went et al.

    Frequent EpCam protein expression in human carcinomas

    Hum Pathol

    (2004)
  • M. Balzar et al.

    Epidermal growth factor-like repeats mediate lateral and reciprocal interactions of Ep-CAM molecules in homophilic adhesions

    Mol Cell Biol

    (2001)
  • S.V. Litvinov et al.

    Ep-CAM: a human epithelial antigen is a homophilic cell–cell adhesion molecule

    J Cell Biol

    (1994)
  • D. Sansonno et al.

    Expression and distribution of a human colon-carcinoma-associated antigen in normal and diseased liver tissue

    Pathobiology

    (1993)
  • C.J. de Boer et al.

    Expression of Ep-CAM in normal, regenerating, metaplastic and neoplastic liver

    J Pathol

    (1999)
  • W.A. Osta et al.

    EpCAM is over-expressed in breast cancer and is a potential target for breast cancer gene therapy

    Cancer Res

    (2004)
  • S.V. Litvinov et al.

    Epithelial cell adhesion molecule (Ep-CAM) modulates cell–cell interactions mediated by classic cadherins

    J Cell Biol

    (1997)
  • J. Behrens et al.

    Dissecting tumor cell invasion: epithelial cells acquire invasive properties after the loss of uvomorulin-mediated cell–cell adhesion

    J Cell Biol

    (1989)
  • A. Armstrong et al.

    EpCAM: a new therapeutic target for an old cancer antigen

    Cancer Biol Ther

    (2003)
There are more references available in the full text version of this article.

Cited by (0)

1

Present address: Novartis Pharma AG, CH-40022 Basel, Switzerland.

View full text