Glypican‐3: a marker and a therapeutic target in hepatocellular carcinoma

Abstract

Glypican-3 (GPC3) is a member of the glypican family. Glypicans are proteoglycans that are attached to the cell surface by a glycosyl-phosphatidylinositol anchor. They regulate the signaling activity of several growth factors, including Wnts. This regulation is based on the ability of glypicans to stimulate or inhibit the interaction of these growth factors with their respective signaling receptors. It has been clearly established that whereas GPC3 is expressed by most hepatocellular carcinomas (HCCs), this glypican is not detected in normal and cirrhotic liver, or in benign hepatic lesions. Consequently, immunostaining of liver biopsies for GPC3 is currently being used by clinical pathologists to confirm HCC diagnosis when the malignant nature of the lesion is difficult to establish. In addition to being a marker of HCC, GPC3 plays a role in the progression of the disease. GPC3 promotes the growth of HCC by stimulating canonical Wnt signaling. It has been proposed that this stimulation is based on the ability of GPC3 to increase the binding of Wnt to its signaling receptor, Frizzled. Two therapeutic approaches for HCC that target GPC3 are currently being tested in phase II clinical trials. One of them is based on the use of a humanized GPC3 monoclonal antibody that inhibits the in vivo growth of HCC xenografts by inducing antibody-dependent cellular cytotoxicity. The second approach employs a vaccine that consists of two GPC3-derived peptides that induce cytotoxic T lymphocytes against these peptides. Targeting of GPC3 might offer a new tool for the treatment of HCC. GlypicansGlypicans are a family of proteoglycans that are attached to the cell surface by a glycosyl-phosphatidylinositol (GPI) anchor [1]. In addition to being found at the cell surface, glypicans can also be detected in the extracellular environment after being released by Notum, a lipase that cleaves GPI anchors [2,3]. Homologs of glypicans are found throughout Eumetazoa [1]. In mammals, six members of this family have been identified (GPC1-GPC6) [4]. Most glypicans carry heparan sulfate (HS) chains, although GPC5 can also display chondroitin sulfate chains [5].Genetic and biochemical studies in various species have shown that glypicans regulate the activity of several growth factors, including Wnts [6,7], Hedgehogs [8,9], bone morphogenetic proteins [10,11] and fibroblast growth factors (FGFs) [12,13]. This regulation is based on the ability of glypicans to stimulate or inhibit the interaction of these growth factors with their Abbreviations AFP, alphafetoprotein; CTL, cytotoxic T lymphocyte; FGF, fibroblast growth factor; GPC3, glypican-3; GPI, glycosyl-phosphatidylinositol; GS, glutamine synthetase; HCC, hepatocellular carcinoma; HS, heparan sulfate; HSP70, heat shock protein 70.

Gene-expression Analysis Identifies Specific Patterns of Dysregulated Molecular Pathways and Genetic Subgroups of Human Hepatocellular Carcinoma

“…In particular, the genes coding for the SPINK1 and GPC3 were recently reported to be (25)(26)(27). As described earlier by our group (28) SPINK1, also known as tumor-associated trypsin inhibitor, was typically overexpressed in HCV-positive HCCs, underlining the theory that SPINK1 may be able to interrupt apoptosis of viralinfected hepatocytes by cellular host defense (29) as one of the postulated mechanisms of this gene in hepatocarcinogegesis.…”

Performance of different biomarkers for the management of hepatocellular carcinoma

“…Codrituzumab (GC33) is a recombinant, humanized monoclonal antibody that binds to human GPC3 with high affinity. The mechanism of the GC33-induced tumor growth inhibition is an antibody-dependent cellular cytotoxicity [33] . A phase I study have already shown its tolerability at doses of 20 mg/kg/week, with little response [34,35] .…”

Evaluating clinical and prognostic implications of Glypican 3 in hepatocellular carcinoma.

“…In the same study, GPC3 expression was negative in sarcomatoid HCC, carcinoid tumors, and cholangiocarcinomas [43]. The reported sensitivity of GPC3 for HCC in the literature ranges from 75% to 100%, and in large-scale trials it ranges from 75% to 85% [26,43,47,[55][56][57].…”