Enhanced glypican-3 expression differentiates the majority of hepatocellular carcinomas from benign hepatic disorders

Zhu, Z.; Friess, Helmut; Wang, L; Abou-Shady, Mohamed; Zimmermann, Arthur; Lander, Arthur D.; Korc, Murray; Kleeff, Jörg; Büchler, Markus W.

doi:10.1136/gut.48.4.558

Cited by 263 publications

(203 citation statements)

References 16 publications

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“…6 The messenger RNA (mRNA) levels of GPC3 have recently been found to be markedly elevated in a large proportion of hepatocellular carcinomas, and this elevation is apparently independent of AFP. 13,16,18 In our immunoblotting and immunostaining of the paraffin-embedded tissue sections, the two monoclonal antibodies against GPC3 (GPC3-C02 and A1836A) specifically recognized GPC3 molecule in the fetal liver and malignant hepatocytes both in vitro and in vivo.…”

Section: Discussionmentioning

confidence: 86%

“…[7][8][9] While studies on ovarian cancer cell lines, mesotheliomas, and breast tumors have demonstrated the downregulation of GPC3, [10][11][12] other investigations on hepatocellular carcinoma have shown a marked elevation of GPC3 mRNA over the level observed in corresponding normal tissues. [13][14][15][16] In the present study, we report the generation of GPC3-C02 and A1836A, a pair of anti-human GPC3 mouse monoclonal antibodies that can detect GPC3 in paraffinembedded tissues by an immunohistochemical technique. When these monoclonal antibodies against GPC3 were applied to malignant and nonmalignant liver tissue samples, we confirmed that they had high sensitivity and specificity not only as diagnostic markers, but as differentiation markers as well.…”

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confidence: 99%

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The glypican 3 oncofetal protein is a promising diagnostic marker for hepatocellular carcinoma

et al. 2005

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Expression profiling of hepatocellular carcinoma has demonstrated that glypican 3 (GPC3), a heparan sulfate proteoglycan anchored to the membrane, is expressed at a markedly elevated level in hepatocellular carcinoma. In this paper, two monoclonal antibodies against GPC3, GPC3-C02 and A1836A, were confirmed to specifically recognize GPC3 molecule in cells from hepatocellular carcinoma and hepatoblastoma cell lines by immunoblotting, and both were confirmed to recognize different epitopes of the GPC3 molecule by epitope mapping. Then, we evaluated the feasibility of GPC3-immunohistochemistry in the pathological diagnosis of benign and malignant hepatocellular lesions by applying these monoclonal antibodies to formalin-fixed and paraffin-embedded specimens. The immunoreactivity turned out to be identical in the two monoclonal antibodies and was thus confirmed to represent the actual expression of the GPC3 molecule. The expression was observed in the fetal liver, but not in normal adult liver, liver cirrhosis or hepatitis except for a tiny focus of a regenerative nodule of fulminant hepatitis. Diffusely positive staining of GPC3 was observed in malignant hepatocytes in hepatoblastomas and in hepatocellular carcinomas (47/56, 84%). GPC3 expression was independent of the differentiation and size of the hepatocellular carcinoma. On the other hand, there was only weak and focal staining in low-grade (2/8) and high-grade dysplastic nodules (6/8). GPC3 immunoreactivity was detected in only one of 23 metastatic lesions of colorectal carcinoma, and its expression was entirely absent in the liver cell adenoma (0/7), carcinoid tumor (0/1), and cholangiocellular carcinoma (0/16). When compared with immunohistochemistry of hepatocyte antigen and alpha-fetoprotein, GPC3-immunohistochemistry was siginificantly much more specific and sensitive for hepatocellular carcinomas. Thus, GPC3 was confirmed to be one of the oncofetal proteins now attracting attention for their promise both as markers of hepatocellular carcinoma in routine histological examination and as targets in monoclonal antibody-based hepatocellular carcinoma therapy. Modern Pathology (2005) 18, 1591-1598.

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Section: Discussionmentioning

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The glypican 3 oncofetal protein is a promising diagnostic marker for hepatocellular carcinoma

et al. 2005

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“…It has been reported that GPC3 messenger RNA levels are increased in HCC [177,178]. To date, a lot of studies reported the usefulness of GPC3 in the differential diagnosis of HCC.…”

Section: Glypican-3mentioning

confidence: 99%

Asian Pacific Association for the Study of the Liver consensus recommendations on hepatocellular carcinoma

et al. 2010

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Introduction The Asian Pacific Association for the Study of the Liver (APASL) convened an international working party on the management of hepatocellular carcinoma (HCC) in December 2008 to develop consensus recommendations. Methods The working party consisted of expert hepatologist, hepatobiliary surgeon, radiologist, and oncologist from Asian-Pacific region, who were requested to make drafts prior to the consensus meeting held at Bali, Indonesia on 4 December 2008. The quality of existing evidence and strength of recommendations were ranked from 1 (highest) to 5 (lowest) and from A (strongest) to D (weakest), respectively, according to the Oxford system of evidence-based approach for developing the consensus statements. 123Hepatol Int (2010) 4: 439-474 DOI 10.1007/s12072-010-9165-7 Results Participants of the consensus meeting assessed the quality of cited studies and assigned grades to the recommendation statements. Finalized recommendations were presented at the fourth APASL single topic conference on viral-related HCC at Bali, Indonesia and approved by the participants of the conference.

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“…12 The gene is frequently methylated in various tumors and cell lines, [13][14][15] suggesting a tumor-suppressive role in tumorigenesis. However, it is also overexpressed in HCC; 16 recently, both Sung et al 17 and Capurro et al 5 reported GPC3 overexpression in HCC both at messenger and protein level. By using a home-made antibody, Yamaouchi et al 18 reported GPC3 weak and focal staining in HCC precursor lesions but diffuse staining in the vast majority of HCCs.…”

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Diagnostic value of HSP70, glypican 3, and glutamine synthetase in hepatocellular nodules in cirrhosis

et al. 2007

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Hepatocellular nodules in cirrhosis include regenerative (large regenerative, LRN) and dysplastic (low and high grade, LGDN and HGDN) nodules, early and grade 1 HCC (eHCC-G1), and overt HCC. The differential diagnosis may be particularly difficult when lesions such as HGDN and eHCC-G1 are involved. We investigated the diagnostic yield of a panel of 3 putative markers of hepatocellular malignancy such as HSP70, glypican 3 (GPC3), and glutamine synthetase (GS). We selected 52 surgically removed nonmalignant nodules (15 LRNs, 15 LGDNs, 22 HGDNs) and 53 HCCs (10 early, 22 grade 1, and 21 grade 2-3) and immunostained them for HSP70, GPC3, and GS. The sensitivity and specificity of the individual markers for the detection of eHCC-G1 were 59% and 86% for GS, 69% and 91% for GPC3, and 78% and 95% for HSP70. We identified 2 main phenotypes: (1) all negative, seen in 100% LRN and LGDN, 73% HGDN and 3% eHCC-G1; (2) all positive, a feature detected in less than half the eHCC-G1. Using a 3-marker panel, when at least 2 of them, regardless which, were positive, the sensitivity and specificity for the detection of eHCC-G1 were respectively 72% and 100%; the most sensitive combination was HSP70؉/GPC3؉ (59%) when a 2-marker panel was used. Conclusion: The adopted panel of 3 markers is very helpful in distinguishing eHCC-G1 from dysplastic nodules arising in cirrhosis. (HEPATOLOGY 2007;45:725-734.)

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Enhanced glypican-3 expression differentiates the majority of hepatocellular carcinomas from benign hepatic disorders

Cited by 263 publications

References 16 publications

The glypican 3 oncofetal protein is a promising diagnostic marker for hepatocellular carcinoma

The glypican 3 oncofetal protein is a promising diagnostic marker for hepatocellular carcinoma

Asian Pacific Association for the Study of the Liver consensus recommendations on hepatocellular carcinoma

Diagnostic value of HSP70, glypican 3, and glutamine synthetase in hepatocellular nodules in cirrhosis

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