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

<jats:p>Glypican‐3 (<jats:styled-content style="fixed-case">GPC</jats:styled-content>3) 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 <jats:styled-content style="fixed-case">GPC</jats:styled-content>3 is expressed by most hepatocellular carcinomas (<jats:styled-content style="fixed-case">HCC</jats:styled-content>s), this glypican is not detected in normal and cirrhotic liver, or in benign hepatic lesions. Consequently, immunostaining of liver biopsies for <jats:styled-content style="fixed-case">GPC</jats:styled-content>3 is currently being used by clinical pathologists to confirm <jats:styled-content style="fixed-case">HCC</jats:styled-content> diagnosis when the malignant nature of the lesion is difficult to establish. In addition to being a marker of <jats:styled-content style="fixed-case">HCC</jats:styled-content>,<jats:styled-content style="fixed-case"> GPC</jats:styled-content>3 plays a role in the progression of the disease. <jats:styled-content style="fixed-case">GPC</jats:styled-content>3 promotes the growth of <jats:styled-content style="fixed-case">HCC</jats:styled-content> by stimulating canonical Wnt signaling. It has been proposed that this stimulation is based on the ability of <jats:styled-content style="fixed-case">GPC</jats:styled-content>3 to increase the binding of Wnt to its signaling receptor, Frizzled. Two therapeutic approaches for <jats:styled-content style="fixed-case">HCC</jats:styled-content> that target <jats:styled-content style="fixed-case">GPC</jats:styled-content>3 are currently being tested in phase <jats:styled-content style="fixed-case">II</jats:styled-content> clinical trials. One of them is based on the use of a humanized <jats:styled-content style="fixed-case">GPC</jats:styled-content>3 monoclonal antibody that inhibits the <jats:italic>in vivo</jats:italic> growth of <jats:styled-content style="fixed-case">HCC</jats:styled-content> xenografts by inducing antibody‐dependent cellular cytotoxicity. The second approach employs a vaccine that consists of two <jats:styled-content style="fixed-case">GPC</jats:styled-content>3‐derived peptides that induce cytotoxic T lymphocytes against these peptides. Targeting of <jats:styled-content style="fixed-case">GPC</jats:styled-content>3 might offer a new tool for the treatment of <jats:styled-content style="fixed-case">HCC</jats:styled-content>.</jats:p>