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

Abstract

Glypican‐3 (GPC 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 GPC 3 is expressed by most hepatocellular carcinomas (HCC s), this glypican is not detected in normal and cirrhotic liver, or in benign hepatic lesions. Consequently, immunostaining of liver biopsies for GPC 3 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, GPC 3 plays a role in the progression of the disease. GPC 3 promotes the growth of HCC by stimulating canonical Wnt signaling. It has been proposed that this stimulation is based on the ability of GPC 3 to increase the binding of Wnt to its signaling receptor, Frizzled. Two therapeutic approaches for HCC that target GPC 3 are currently being tested in phase II clinical trials. One of them is based on the use of a humanized GPC 3 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 GPC 3‐derived peptides that induce cytotoxic T lymphocytes against these peptides. Targeting of GPC 3 might offer a new tool for the treatment of HCC.