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Enhanced Glypican-3 Expression Diverentiates the Majority of Hepatocellular Carcinomas from Benign Hepatic Disorders

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Enhanced Glypican-3 Expression Diverentiates the Majority of Hepatocellular Carcinomas from Benign Hepatic Disorders 558 Gut 2001;48:558–564 Enhanced glypican-3 expression diVerentiates the majority of hepatocellular carcinomas from benign hepatic disorders Gut: first published as 10.1136/gut.48.4.558 on 1 April 2001. Downloaded from Z-W Zhu, H Friess, L Wang, M Abou-Shady, A Zimmermann, A D Lander, M Korc, J KleeV, M W Büchler Abstract Asian and Western countries.1 Surgical resec- Background/aims—Hepatocellular carci- tion remains the treatment of choice for these noma (HCC) is a common malignant tumours. Unfortunately, only 10–20% of tumour worldwide, and its diVerential primary liver tumours are found to be resect- diagnosis from benign lesions of the liver able at the time of diagnosis.2 Advances in is often diYcult yet of great clinical radiological imaging over the past two decades importance. In the present study, we ana- have focused attention on early detection of lysed whether glypican-3 is useful in hepatic nodular lesions. Various pathological diVerentiating between benign and malig- entities with a nodular appearance are pre- nant liver diseases and whether it influ- dominantly composed of hepatocytes or ences the growth behaviour of HCC. tumour cells of hepatocytic origin, including Methods—Northern blot analysis and in benign and malignant neoplasms as well as situ hybridisation. tumour-like lesions such as focal nodular Results—Northern blot analysis indicated hyperplasia (FNH). The diVerential diagnosis that expression of glypican-3 mRNA was of these nodules is often diYcult, especially in either low or absent in normal liver, in view of the limited material which is obtained 3 focal nodular hyperplasia (FNH), and in by needle biopsy. FNH and liver cirrhosis are liver cirrhosis. In contrast, expression of the most common benign liver diseases, which glypican-3 mRNA was markedly increased may present with a nodular appearance. in 20 of 30 and moderately increased in DiVerentiating between focal nodules in FNH or regenerative nodules in cirrhotic livers and Department of five of 30 HCC samples. The average Visceral and malignant nodules is of great clinical increase in glypican-3 mRNA expression 4 Transplantation in HCC was significant compared with importance because of the resulting therapeu- Surgery, University of expression in normal liver (21.7-fold in- tic consequences. However, diVerentiation http://gut.bmj.com/ Bern, Inselspital, between benign and malignant nodules, espe- Bern, Switzerland crease, p<0.01). In comparison with FNH or liver cirrhosis, glypican-3 mRNA ex- cially of the nodules of liver cirrhosis, is often Z-W Zhu di cult and even the sensitive and specific H Friess pression in HCC was increased 7.2- Y L Wang (p<0.05) and 10.8-fold (p<0.01), respec- magnetic resonance imaging has its limitations M Abou-Shady tively. In addition, pushing HCCs exhib- in these cases. J KleeV ited significantly higher glypican-3 mRNA Glypican-3 belongs to the glypican family of M W Büchler GPI anchored heparansulphate proteoglycans expression than invading tumours on October 4, 2021 by guest. Protected copyright. (p<0.05). In situ hybridisation analysis (HSPGs) which plays an important role in cel- Institute of Pathology, lular growth, cell diVerentiation, and cell University of Bern, demonstrated weak expression of Inselspital, Bern, glypican-3 mRNA in normal hepatocytes migration. To date, six distinct members of the human glypican family have been identified, Switzerland and bile ductular cells, and weak to A Zimmermann and their importance in various diseases has occasionally moderate signals in hepato- recently been recognised.5 Mutations in the cytes forming nodules of liver cirrhosis Departments of glypican-3 gene are responsible for the and in regenerated hepatic nodules of Medicine, Biological Simpson-Golabi-Behmel syndrome in humans Chemistry, and FNH. In contrast, glypican-3 in situ which is characterised by pre- and postnatal Pharmacology, hybridisation signals were intense in he- overgrowth and by a number of other abnor- University of patic cancer cells with even higher levels California, Irvine, malities.67In addition, glypicans seem to influ- in pushing HCCs than in invading HCCs. California, USA ence tumour pathogenesis in various human Conclusions—These findings suggest that M Korc malignancies.8–10 For example, in mesothelio- glypican-3, in many cases, has the poten- mas, induction of glypican-3 expression inhib- Department of tial to diVerentiate between benign and Developmental and its cell growth, and glypican-3 mRNA levels are malignant liver diseases. significantly reduced in human malignant mes- Cell Biology and (Gut 2001;48:558–564) Developmental Biology othelioma tumours and cell lines.810 In addi- Center, University of Keywords: focal nodular hyperplasia; liver cirrhosis; tion, in MCF-7 breast cancer cells, enhanced California, Irvine, hepatocellular cancer; glypican-3 glypican-3 expression leads to apoptosis.8 California, USA A D Lander : HCC, Correspondence to: Hepatocellular carcinoma (HCC) is one of the Abbreviations used in this paper Dr H Friess. most severe sequelae of chronic liver disease. In hepatocellular carcinoma; FNH, focal nodular [email protected] hyperplasia; HSPGs, heparansulphate proteoglycans; spite of recent therapeutic advances, this HGF, hepatocyte growth factor; EGF, epidermal Accepted for publication malignancy continues to be a significant cause growth factor; HB-EGF, heparin binding EGF-like 17 October 2000 of cancer related morbidity and mortality in growth factor; SDS, sodium dodecyl sulphate. www.gutjnl.com Glypican-3 expression and HCC 559 Normal Liver not in benign hepatic disorders, and that there livercirrhosis HCC FNH are diVerences in its expression between push- ing and invading tumours. These data suggest that glypican-3 may be useful in diVerentiating between HCC and benign hepatic nodules and Gut: first published as 10.1136/gut.48.4.558 on 1 April 2001. Downloaded from Glypican-1 that its presence may influence the growth (3.7 kb) characteristics of HCCs. Materials and methods Glypican-3 HUMAN LIVER SAMPLES (2.4 kb) Normal human liver tissue samples (10 female and five male donors; median age 53 years; range 28–56) were obtained from previously healthy organ donors (n=9) and from patients undergoing hemihepatectomy due to colorectal Glypican-4 metastasis (n=6). In the case of liver resection, (4.6 and 3.4 kb) tissue specimens were taken at the farthest dis- tance from the metastasis. Histological analysis of the liver specimens revealed normal liver tis- sue in all cases. FNH tissues were obtained from three male and four female patients Glypican-6 (median age 58 years; range 39–68) who (5.8 kb) underwent liver resection due to a growing nodular hepatic tumour. Liver cirrhosis tissue samples were obtained from 28 patients (20 males and eight female; median age 63 years; range 32–72), 21 of whom underwent liver transplantation (eight hepatitis B, 10 hepatitis 7S C, and three alcoholic) and seven of whom underwent surgery and hepatic exploration/ resection due to unclear hepatic nodules which were identified as liver cirrhosis by histopatho- logical examination. HCCs were obtained from Figure 1 Northern blot analysis of glypican-1, -3, -4, and -6 in normal liver, liver 30 patients (20 males and 10 female; median cirrhosis, hepatocellular carcinoma (HCC), and focal nodular hyperplasia (FNH). Total http://gut.bmj.com/ RNA (20 µg) was size fractionated, blotted, and hybridised with the indicated 32P labelled age 64 years; range 33–78) undergoing liver probes. resection. According to the TNM (tumour- node-metastasis) classification and histopatho- Glypican-3 expression is lost in some ovarian logical grading of the UICC (Union Interna- cancer cell lines, and restoration of glypican-3 tionale Contre le Cancer),19 there were no stage expression inhibits the growth of these cells, I tumours, two stage II tumours, 14 stage III suggesting that glypican-3 may function as a tumours, and 14 stage IV tumours. Tumour tumour suppressor in ovarian cancer.9 Recent grading showed four well diVerentiated tu- on October 4, 2021 by guest. Protected copyright. studies have shown that a variety of growth mours (grade 1), 14 moderately diVerentiated factors and their receptors, such as hepatocyte tumours (grade 2), 11 poorly diVerentiated growth factor (HGF), c-met, epidermal growth tumours (grade 3), and one undiVerentiated factor (EGF), and heparin binding EGF-like tumour (grade 4). Nineteen tumours were growth factor (HB-EGF) are upregulated in pushing carcinomas and 11 were invading HCC.11–13 Inasmuch as HGF and HB-EGF tumours (table 1), which were classified as pre- require membrane bound HSPGs as a co- viously described.18 Freshly removed tissue receptor for their signalling, the presence of samples were fixed in 5% formaldehyde glypican may regulate the growth behaviour of solution for 12–24 hours and paraYn embed- HCC. Furthermore, there is also increasing ded for histological analysis and in situ evidence that HSPGs, such as syndecan-1, -2, hybridisation. In addition, tissue samples were -3, or -4, may play an important role in the frozen in liquid nitrogen immediately on surgi- normal liver, in chronic liver disease, and in the ° 14–16 cal removal and maintained at −80 C until use carcinogenesis of primary liver tumours. for RNA extraction. All studies were approved Furthermore, preliminary results indicate that by the ethics committee of the University of glypican-3 is diVerentially expressed in HCC Bern. compared with the normal liver and that it may serve as a tumour marker in this malignancy.17 In the present study, we evaluated expression NORTHERN BLOT ANALYSIS of glypican-3 mRNA in two morphological Total RNA was extracted using the guanidin- subtypes of HCC—pushing and invading ium isothiocyanate method20 21 followed by tumours, as described previously18 —compared electrophoresis under denaturing conditions in with normal liver tissues as well as with the a 1.2% agarose/1.8 M formaldehyde gel.20 21 common benign liver diseases FNH and liver RNA was electrotransferred onto nylon mem- cirrhosis.
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