Claudin-4 differentiates biliary tract cancers from hepatocellular carcinomas

Abstract

The recently identified claudins are dominant components of tight junctions, responsible for cell adhesion, polarity and paracellular permeability. Certain claudins have been shown to have relevance in tumor development, with some of them, especially claudin-4, even suggested as future therapeutic target. The aim of the present study was to analyze the expression of claudin-4 in the biliary tree, biliary tract cancers and hepatocellular carcinomas. A total of 107 cases were studied: 53 biliary tract cancers, 50 hepatocellular carcinomas, 10 normal liver and 10 normal extrahepatic biliary duct samples. Immunohistochemical analysis was performed on conventional specimens and on tissue microarrays as well. Claudin-4 was further investigated by Western blot analysis and real-time RT-PCR. Intense membranous immunolabeling was found for claudin-4 in all biliary tract cancers unrelated to the primary site of origin, namely intrahepatic, extrahepatic or gallbladder cancers. Normal biliary epithelium showed weak positivity for claudin-4. In contrast, normal hepatocytes and tumor cells of hepatocellular carcinomas did not express claudin-4. The results of Western immunoblot analysis and real-time RT-PCR were in correlation with the immunohistochemical findings. Cytokeratins, as CK7 (92%) and CK19 (83%) were mostly positive in biliary tract cancers, however, one-third of hepatocellular carcinomas also expressed CK7 (34%). HSA antibody (HepPar1) reacted with the majority of hepatocellular carcinomas (86%), while being positive in a low percentage of the biliary tract cancers (8%). In conclusion, this is the first report of a significantly increased claudin-4 expression in biliary tract cancers, which represents a novel feature of tumors of biliary tract origin. Claudin-4 expression seems to be a useful marker in differentiating biliary tract cancers from hepatocellular carcinomas and could well become a potential diagnostic tool.

Tight junctions in thyroid carcinogenesis: diverse expression of claudin-1, claudin-4, claudin-7 and occludin in thyroid neoplasms

“…Formalin-fixed, paraffin-embedded thyroid tissues of 91 thyroidectomy specimens resected from an equal number of patients for therapeutic purposes, as well as the pathology report for each patient, were retrieved from the files of the Department of 24 were recorded. Additionally, follow-up data were available for 33 patients (1 patient with papillary microcarcinoma, 13 with papillary carcinoma, 7 with medullary carcinoma, 2 with undifferentiated carcinoma and 10 with follicular carcinoma) and the disease-free survival and overall survival was determined.…”

“…Regarding tumor stage, 24 32 tumors were T1, 14 T2, 21 T3 and 9 T4. In 13 cases, lymph node sampling had been performed.…”

Claudin-1 and claudin-5 expression patterns differentiate lung squamous cell carcinomas from adenocarcinomas

“…Several studies have shown an altered expression of CLDNs in human tumors, including tumors of the gastrointestinal tract, 8,9 ovary, 10 pancreas, 11 breast, 12,13 epidermis, 14 liver, 15,16 uterus 17 and prostate. 18 Little information is available on the expression of cytoplasmic tight junction proteins in human cancers, [19][20][21][22] and only one study has been published about the immunohistochemical localization of a tight junction protein (occludin (OCLN)) in lung tumors.…”

Expression of Tight Junction Components in Hepatocyte-Like Cells Differentiated from Human Embryonic Stem Cells

“…In the liver, claudin-1 can be detected in both hepatocytes and cholangiocytes [27,28], however, claudin-4 can be mainly found in cholangiocytes and tumors of cholangiocyte origin [7,29]. Claudin-5 component is typically expressed in the endothelial cells [22], however it can be expressed in certain tumors such as in fibrolamellar carcinoma of the liver [27].…”

“…Parenchymal cells of the liver, i.e., hepatocytes and bile duct cells (cholangiocytes) play distinct roles in diverse hepatic functions, thus, they differ from each other in several aspects including expression pattern of cytokeratins, ABC transporter proteins, and tight junction (TJ) components [7][8][9].…”