Glypican-3: a new target for cancer immunotherapy

Abstract

Hepatocellular carcinoma (HCC) remains a common malignant cancer worldwide. There is an urgent need to identify new molecular targets for the development of novel therapeutic approaches. Herein, we review the structure, function and biology of glypican-3 (GPC3) and its role in human cancer with a focus on its potential as a therapeutic target for immunotherapy. GPC3 is a cell-surface protein that is over-expressed in HCC. Loss-of-function mutations of GPC3 cause Simpson-Golabi-Behmel syndrome (SGBS), a rare X-linked overgrowth condition. GPC3 binds Wnt and Hedgehog (Hh) signalling proteins. GPC3 is also able to bind basic growth factors such as fibroblast growth factor 2 through its heparan sulphate glycan chains. GPC3 is a promising candidate for liver cancer therapy given that it shows high expression in HCC. An anti-GPC3 monoclonal antibody has shown anti-cancer activity in mice and its humanised IgG molecule is currently undergoing clinical evaluation in patients with HCC. There is also evidence that soluble GPC3 may be a useful serum biomarker for HCC.

Fig. 1

Schematic of the GPC3 protein. The human GPC3 gene encodes a 70 kDa precursor protein of 580 amino acids. Upon translocation into the endoplasmic reticulum, the N-terminal signal peptide (SS; residues 1–24) and the C-terminal GPI anchor addition signal (a predicted cleavage site: S560) are removed and the latter is replaced with a GPI anchor. The GPC3 precursor is cleaved into two subunits, NH₂ terminus (residues Q25 – R358) and the GPI-anchored membrane-bound COOH terminus starting from S359. The three N-linked glycans (black lollipops; N124, N241 and N418) are indicated.

Fig. 2

GPC3 expression in human primary liver tumors. GPC3 expression was detected by immunohistochemistry using mAb 1G12 in tissue specimens of patients with HCC (A); CCA (B); and normal liver tissue (C). Brown staining indicates GPC3 protein expression.