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. Here, 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, a rare X-linked overgrowth condition. GPC3 binds Wnt and Hedgehog signaling proteins. GPC3 is also able to bind basic growth factors such as fibroblast growth factor 2 through its heparan sulfate 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 humanized 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.

Primary and Metastatic Tumours of the Liver: Expanding Scope of Morphological and Immunohistochemical Details in the Biopsy

“…Glypican-3 is a cell surface protein [1] that is involved in the control of cell proliferation and survival. Glypican-3-knockout mice exhibit alterations in Wnt signalling [45].…”

“…In addition, 10% of gastric cancer cases are positive for glypican-3 [55]. In melanoma, 80% of tumours contain detectable level of glypican-3 protein and mRNA [1]. Regarding ovarian cancer, the rate of glypican expression could be as high as 18% of all ovarian cancer cases and 60% of clear cell carcinoma cases [51].…”

“…Glypican-3 also interacts with Hedgehog signalling pathway [46]. In the practical surgical pathology, the value of glypican-3 is associated with the cancer diagnostics as it is expressed in 70-75% of HCC but not in benign liver tissue [48][49] or cholangiocellular carcinoma [1]. Hepatoblastoma can be positive as well.…”

“…Immunotherapy could be guided towards glypican-3; the present research is exploring both antibody and cell-based immunological mechanisms [64][65]. Cancer vaccine could be generated against this molecule [1]. Glypican-3 is among genes that are distinctly expressed in liver cancer stem cells; it is suggested that glypican could be promising candidate for gene therapy without inducing damage to normal liver stem cells [66].…”

“…Immunohistochemical markers as glypican-3 [1], Hep Par 1 [3,6], CD10 [3], alpha-fetoprotein [6] and TTF-1 [16] are useful in the HCC diagnostics. Alterations of CD31 and CD34-positive endothelial cell network reflect vascular remodelling during hepatic carcinogenesis [7].…”