Glycoprotein
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Glypican-3: A Novel Marker for the Diagnosis of Hepatocellular Carcinoma

 Hepatocellular carcinoma (HCC) is one of the most common cancers in the world (more than 500.000 deaths/year). Surgical resection remains the treatment of choice for these tumors, but only 10-20 % of primaries HCCs are resectable at time of diagnosis. Therefore early detection of HCC is a critical goal to improve the poor prognosis of this malignancy, and screening programs of patients at risk, such as chronic carriers of hepatitis B and C, are justified.

Currently, various imaging techniques are being used for the diagnosis of HCC. These techniques include ultrasonography, computed tomography scanning, and magnetic resonance. However, these techniques are not very good at distinguishing benign hepatic lesions such as dysplastic nodules and cirrhotic macronodules from HCC. Thus, despite the advances in diagnostic imaging, there is still a need for suitable biochemical markers for the early detection of HCC.

Serum a-fetoprotein (AFP) is the only molecular marker that has been widely used for the diagnosis of HCC. However, this marker is not very sensitive for the detection of small tumors, and its levels in the serum are also increased in a significant proportion of patients with benign liver disease. Thus the identification of novel biochemical markers for HCC remains an important goal for many laboratories around the world. Since HCC is highly heterogeneous, it is currently thought that it is unlikely that a single molecular marker produced by all HCCs will be found, and that most likely the combined use of more than one marker will offer a better approach for efficient detection.

Our laboratory has recently reported that glypican-3 (GPC3) can be considered a serum and histochemical marker for HCC 1). By immunostaining HCC tissue sections with an anti-GPC3 monoclonal antibody we found that this protein is expressed in 72 % of HCCs (see Fig. 1), whereas it is not detectable in hepatocytes from normal liver and benign liver diseases. More importantly, by using an ELISA we established that whereas GPC3 is undetectable in the serum of healthy donors and patients with hepatitis, its levels are significantly increased in 53 % of patients with HCC. In addition, only 5 % of patients with liver cirrhosis but no HCC displayed elevated levels of serum GPC3. Interestingly, in most cases there was no correlation between GPC3 and AFP values, and at least one of the two markers was elevated in 82 % of HCC patients. This suggests that the simultaneous measurement of AFP and GPC3 could provide a significantly improved test for the detection of HCC compared to the measurement of AFP alone.

The role of GPC3 as a marker for HCC has been recently confirmed by other two laboratories 2),3). Moreover, these investigators have also confirmed the lack of overlap between the AFP and GPC3 values.
 Fig.1.HCC tissue section stained with a GPC3 antibody.
Only the malignant nodules are positive.Non-malignant cells are negative.
 
Jorge Filmus (Sunnybrook and Women’s College Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada)
References (1) Capurro M, Wanless IR, Sherman M, Deboer G, Shi W, Miyoshi E, Filmus J: Glypican-3: a novel serum and histochemical marker for hepatocellular carcinoma. Gastroenterology, 125, 89-97, 2003.
(2) Nakatsura T, Yoshitake Y, Senju S, Monji M, Komori H, Motomura Y, Hosaka S, Beppu T, Ishiko T, Kamohara H, Ashihara H, Katagiri T, Furukawa Y, Fujiyama S, Ogawa M, Nakamura Y, Nishimura Y: Glypican-3, overexpressed specifically in human hepatocellular carcinoma, is a novel tumor marker. Biochem.Biophys.Res.Commun. 306, 16-25, 2003.
(3) Hippo Y, Watanabe K, Watanabe A, Midorikawa Y, Yamamoto S, Ihara S, Tokita S, Iwanari H, Ito Y, Nakano K, Nezu J, Tsunoda H, Yoshino T, Ohizumi I, Tsuchiya M, Ohnishi S, Makuuchi M, Hamakubo T, Kodama T, Aburatani H: Identification of soluble NH2-terminal fragment of glypican-3 as a serological marker for early-stage hepatocellular carcinoma. Cancer Res. 64, 2418-2423, 2004.
Links PG-A02 Syndecans and Glypicans – Cell surface proteoglycans (Tetsuhito Kojima)
Jul. 15, 2004

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