Sejtadhéziós molekulák szerepe a daganatok, kiemelten a májrákok patogenezisében = The role of cell adhesion molecules in the pathogenesis of tumors, with emphasis on liver cancers

A sejtkapcsolatok a daganatokban megváltoznak, különösen a tight junction (TJ) gerincét alkotó claudin (CLDN) fehérje család komponensei, melynek 24 típusa ismert emberben. Több daganatban elsőként vizsgálatuk a CLDN expresszió eltéréseit protein és mRNS szinten. Megállapítottuk, hogy az egyes CLDN-ok expressziója jelentősen nő a nyelőcső rákban, a Barrett oesophagusban és adenocarcinomában (ACC). A CLDN mintázat elkülöníti a hepatoblastoma és endometrialis carcinoma formáit, a pancreas endocrin tumorait és a ductalis ACC-t, valamint a tüdőtumorokat, a primer és metasztatikus májdaganatokat. Egyes extracellularis matrix (ECM) komponensek, így az agrin, valamint a matrilin2 expressziója és lokalizációja megváltozik a cirrhosisban és májrákokban. Fenti vizsgálatok jelentősége, hogy számos daganatban feltárta a sejtkapcsolatok és ECM változásait és igazolta, hogy az eltérések jellemzők az egyes tumorokra, követik a kiindulási szövet sejtkapcsoló struktúráinak fehérje összetételét, bár expressziójuk mértéke változik. A vizsgált daganatok CLDN mintázata diagnosztikus értékű. A vizsgálatok igazolták, hogy a TJ dinamikusan változó protein összetétele a carcinogenesis során bonyolult funkcionális változást takar és az egyes összetevők aránya és egymással való kapcsolata a döntő az intakt sejtkapcsolat kialakulásában. | Cell junctions change in tumors, especially the components of the claudin (CLDN) protein family (24 types of which are known in humans) forming the backbone of tight junctions (TJ). We were first to study CLDN expression alterations in several tumors at protein and mRNA levels. Our studies confirmed that expression of certain CLDNs shows significant increase in oesophageal squamous cell carcinoma, Barrett?s oesophagus and adenocarcinoma (ACC). The CLDN pattern differentiates components of hepatoblastomas and 2 types of endometrial carcinomas, endocrine tumors of the pancreas, ductal ACCs, lung tumors, primary and metastatic liver tumors. Certain extracellular matrix (ECM) components, as agrin, matrilin-2 exhibited altered expression and location in cirrhosis and liver cancers. Our observations revealed TJ and ECM changes in several tumor types, confirming that the changes are characteristic to the tumor. The CLDN pattern of the studied tumors are of diagnostic significance. Our studies confirmed that the dynamically changing protein composition of TJs covers complex functional changes during carcinogenesis, and the proportion and interrelationship of various components are decisive in the development of intact TJs

Expression of Matrilin-2 in Liver Cirrhosis and Hepatocellular Carcinoma

The recently described matrilin protein family is part of the extracellular matrix, their pathophysiological role as well as distribution in liver diseases, however, have not yet been studied. Considering that matrilins have been found to play role in cell growth and tissue remodeling, their possible involvement in carcinogenesis has been raised. The main objective of this study was to investigate the changes in matrilin-2 expression which is one of the main components of basement membranes. Thirty-five cases of surgically resected hepatocellular carcinomas, 35 corresponding surrounding liver tissues and 10 normal liver samples were used for the study. In 15 of 35 cases the tumor developed on the basis of cirrhosis. Matrilin-2 protein expression was detected in normal liver around bile ducts, portal blood vessels, while sinusoids were negative by immunohistochemistry. Cirrhotic surrounding tissue showed intensive matrilin-2 staining along the sinusoids. Tumorous neovasculature was found strongly positive by immunohistochemistry. No differences, however, were detected by morphometry regarding the amount of protein expression based on the grade of hepatocellular carcinomas. Real-time RT-PCR did not show significant differences in matrilin-2 mRNA expression between normal, cirrhotic and tumor samples. This suggests posttranslational modification of matrilin-2 manifesting in altered distribution in liver fibrosis. Our data indicate that matrilin-2 is a novel basement membrane component in the liver, which is synthetised during sinusoidal "capillarization" in cirrhosis and in hepatocellular carcinoma. This is the first report to describe the expression and distribution of matrilin-2 in human normal and cirrhotic liver as well as in hepatocellular carcinoma

Increased Expression of Claudin-1 and Claudin-7 in Liver Cirrhosis and Hepatocellular Carcinoma.

Claudins have been reported to be differentially regulated in malignancies and implicated in the process of carcinogenesis and tumor progression. Claudin-1 has been described as key factor in the entry of hepatitis C virus (HCV) into hepatocytes and as promoter of epithelial-mesenchymal transition in liver cells. The objective of the current study was to characterize claudin expression in hepatocellular carcinoma (HCC) as well as HCC-surrounding and normal liver samples with respect to cirrhosis and HCV infection. Expression of claudin-1, -2, -3, -4, and -7 was measured by morphometric analysis of immunohistochemistry, and Western blotting in 30 HCCs with 30 corresponding non-tumorous tissues and 6 normal livers. Claudin-1 and -7 protein expression was found significantly elevated in cirrhosis when compared with non-cirrhotic liver. HCCs developed in cirrhotic livers showed even higher expression of claudin-1 contrary to decreased claudin-7 expression when compared with cirrhosis. With reference to HCV status, HCCs or surrounding livers of HCV-infected samples did not show significant alterations in claudin expression when compared with HCV-negative specimens. Cirrhotic transformation associates with elevated claudin-1 and -7 expressions in both non-tumorous liver and HCC. The fact that no significant differences in claudin expression were found regarding HCV-positivity in our sample set suggests that HCV infection alone does not induce a major increase in the total amount of its entry co-factor claudin-1. Increased expression of claudin-1 seems to be a consequence of cirrhotic transformation and might contribute to a more effective HCV entry and malignant transformation