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Apical Membrane Expression of Distinct Sulfated Glycans Represents a Novel Marker of Cholangiolocellular Carcinoma

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Apical Membrane Expression of Distinct Sulfated Glycans Represents a Novel Marker of Cholangiolocellular Carcinoma Laboratory Investigation (2016) 96, 1246–1255 © 2016 USCAP, Inc All rights reserved 0023-6837/16 Apical membrane expression of distinct sulfated glycans represents a novel marker of cholangiolocellular carcinoma Hitomi Hoshino1, Makoto Ohta2, Makoto Ito3, Kenji Uchimura4, Yasuhiro Sakai5, Takeshi Uehara6, Shulin Low1, Mana Fukushima5 and Motohiro Kobayashi1 Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver neoplasm, followed by hepatocellular carcinoma. ICC can be further subclassified as (i) perihilar and (ii) peripheral types, the latter histologically resembling small-sized intrahepatic bile ducts, such as interlobular bile ducts, cholangioles/ductules and the canals of Hering. Cholangiolocellular carcinoma (CoCC), now classified by the World Health Organization as a subtype of combined hepatocellular-cholangiocarcinoma, is currently regarded as a subtype of peripheral-type ICC. The present study was undertaken to determine whether sulfated glycans recognized by the MECA-79 monoclonal antibody could serve as a CoCC marker. Using immunohistochemistry, we show that MECA-79 sulfated glycans are preferentially expressed at the apical membrane of cholangiocytes found in small-sized intrahepatic bile ducts in normal liver and in canalicular structures formed in CoCC. We also report that apical membrane MECA-79 sulfated glycan expression colocalizes with that of mucin 1 (MUC1) core proteins. We also present immunoblotting of Chinese hamster ovary cells overexpressing FLAG- tagged MUC1 to show that MUC1 serves as a MECA-79 scaffold. Furthermore, we report that SSP-25 human ICC cells overexpressing N-acetylglucosamine-6-O-sulfotransferase 2 (GlcNAc6ST-2), but not GlcNAc6ST-1, exhibit membrane expression of MECA-79 sulfated glycans, suggesting that GlcNAc6ST-2 catalyzes MECA-79 epitope biosynthesis in cholangiocytes. Moreover, both wild-type and GlcNAc6ST-1 knockout mice exhibit apical membrane MECA-79 expression in small-sized intrahepatic bile ducts, namely interlobular bile ducts, whereas MECA-79 expression was completely absent in comparable tissues from GlcNAc6ST-1 and GlcNAc6ST-2 double knockout mice. These data collectively indicate that apical membrane localization of MUC1 proteins decorated with GlcNAc6ST-2-dependent MECA-79 sulfated glycans may mark cholangiocytes with cholangiolar/ductular differentiation and could serve as a useful CoCC marker. Laboratory Investigation (2016) 96, 1246–1255; doi:10.1038/labinvest.2016.104; published online 17 October 2016 Intrahepatic cholangiocarcinoma (ICC) is the second most type originates in peripheral small-sized intrahepatic bile common primary liver neoplasm, followed by hepatocellular ducts, such as interlobular bile ducts, cholangioles/ductules, carcinoma (HCC).1,2 ICC can be further subclassified into (i) and the canals of Hering,8 which are lined with non-mucous- perihilar type (also called large bile duct type) and (ii) producing cuboidal cholangiocytes.1,2 peripheral type (also called small bile duct type or Cholangiolocellular carcinoma (CoCC) (also called bile cholangiolar type),2–6 and both subtypes are thought to arise ductular carcinoma3), classified as cholangiolocellular type of from topologically different intrahepatic bile ducts.5 As combined hepatocellular-cholangiocarcinoma with stem cell named, perihilar type emerges from perihilar large-sized features in the latest (4th) edition of the World Health intrahepatic bile ducts, such as segmental and septal bile Organization (WHO) classification,9 was first described by ducts, which are lined with mucous-producing tall cylindrical Steiner and Higginson in 1959.10 For over a half century since cholangiocytes (biliary epithelial cells),7 whereas peripheral then, CoCC has been categorized as a special subtype of 1Department of Tumor Pathology, Faculty of Medical Sciences, University of Fukui, Eiheiji, Japan; 2Department of Pathology, Fukui Red Cross Hospital, Fukui, Japan; 3Department of Pathology and Laboratory Medicine, Kariya Toyota General Hospital, Kariya, Japan; 4Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan; 5Department of Molecular Pathology, Shinshu University Graduate School of Medicine, Matsumoto, Japan and 6Department of Laboratory Medicine, Shinshu University School of Medicine, Matsumoto, Japan Correspondence: Professor M Kobayashi, MD, PhD, Department of Tumor Pathology, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka-Shimoaizuki, Eiheiji, Fukui 910-1193, Japan. E-mail: [email protected] Received 8 March 2016; revised 25 August 2016; accepted 30 August 2016 1246 Laboratory Investigation | Volume 96 December 2016 | www.laboratoryinvestigation.org Apical sulfated glycan expression in CoCC H Hoshino et al peripheral-type ICC.5,6,11 Histologically, CoCC is described as Previously, we demonstrated that HEV-like vessels induced well-differentiated adenocarcinoma forming anastomosed in type 1 autoimmune pancreatitis were positively immuno- antler-like glands with edematous fine fibrous stroma, stained by MECA-79 monoclonal antibody.33 In that study, resembling a ductular reaction seen in several acute and we unexpectedly discovered a sizable fraction of interlobular chronic liver diseases, including massive hepatic necrosis.10–12 pancreatic ducts that were also MECA-79 positive.33 Thus, we CoCC is thought to originate in the peripherally distributed concluded that the biliary system, which is connected to the biliary ductular system, including cholangioles/ductules pancreatic duct system to form the pancreaticobiliary system,7 and the canals of Hering,8 where hepatic progenitor cells is also decorated with MECA-79 sulfated glycans. It remained (HPCs) are located.5,11,12 As HPCs can differentiate into unknown whether MUC1 was the scaffold protein for those either hepatocytes or cholangiocytes,11 they are thought to be glycans. the origin of combined hepatocellular-cholangiocarcinoma. In the present study, we demonstrate that MECA-79 However, the histogenesis of CoCC and combined sulfated glycans are preferentially expressed in apical hepatocellular-cholangiocarcinoma remains controversial, membranes of small-sized intrahepatic bile ducts as well as and definite conclusions relevant to diagnostic criteria for on canalicular structures in CoCC. Moreover, apical mem- these diseases have not yet been reached. brane MECA-79 positivity colocalized with MUC1 core Several molecules have been proposed as CoCC markers, proteins. These findings suggest that apical membrane including cytokeratin 19,12,13 neural cell adhesion molecule localization of MUC1 protein decorated with MECA-79 1,14 N-cadherin,1 and mucin 1 (MUC1).7,15,16 Among them, sulfated glycans may be a distinct feature of cholangiocytes MUC1, also known as epithelial membrane antigen (EMA), is with cholangiolar/ductular differentiation and serve as a generally thought to be most useful to distinguish CoCC from CoCC marker. perihilar-type ICC: CoCC shows an apical membrane MUC1 staining pattern, whereas MUC1 staining is diffuse and MATERIALS AND METHODS cytoplasmic in perihilar-type ICC.7,15,16 Human Tissue Samples Transmembrane MUC1 protein is present in the apical In the present study, the diagnosis of CoCC was made when membrane of glandular epithelial cells in numerous organs cases of peripheral-type ICC (in a broad sense) fulfilled all and tissues, where it functions primarily in lubrication and four criteria as follows: (i) well-differentiated adenocar- cell protection.17,18 MUC1 is translated as a single polypeptide cinoma forming small monotonous and/or anastomosing chain that undergoes autoproteolytic cleavage to form two glands, (ii) which are composed of cuboidal non-mucous- subunits that interact non-covalently.19 The large N-terminal producing neoplastic cholangiocytes, (iii) with fine fibrous subunit consists of a long extracellular domain, and the small stroma, and (iv) luminal surface of canalicular structures were C-terminal subunit contains a short extracellular domain, a positively immunostained by MUC1. Formalin-fixed, transmembrane region and a cytoplasmic tail.20 The larger paraffin-embedded tissue blocks of CoCC liver tissue subunit harbors a serine/threonine-rich region with a highly (n = 20; 6 males and 14 females; age range, 48–85 years; polymorphic sequence motif termed the variable number of median, 71 years) were retrieved from the pathological tandem repeats (VNTR), which is often extensively O- archives of Shinshu University Hospital and its affiliated glycosylated with a battery of Lewis blood group-related hospitals. Liver tissue blocks with peripheral-type ICC carbohydrate antigens, such as sialyl Lewis A (also known as (n = 26; 15 males and 11 females; age range, 28–85 years; CA19-9) and sialyl Lewis X.17,21,22 median, 70 years), perihilar-type ICC (n = 25; 18 males and 7 A sulfated form of sialyl Lewis X, specifically 6-sulfo sialyl females; age range, 54–85 years; median, 65 years) and HCC Lewis X, is displayed on high endothelial venules (HEVs) in (n = 25; 24 males and 1 female; age range, 44–85 years; secondary lymphoid organs such as lymph nodes, tonsils and median, 68 years) were also retrieved as controls. Detailed Peyer’s patches, and functions in physiological recirculation clinicopathological information, including background liver of lymphocytes from the bloodstream into lymphoid organs, a diseases, of these patients is listed in Supplementary Table 1. process termed lymphocyte 'homing.'23 Although absent Analysis of human
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