NDLI: Inactivation of Wnt signaling by a human antibody that recognizes the heparan sulfate chains of glypican-3 for liver cancer therapy

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Gao, Wei Kim, Heungnam Feng, Mingqian Phung, Yen Xavier, Charles P. Rubin, Jeffrey S. Ho, Mitchell
Description	Country affiliation: Moldova Author Affiliation: Gao W ( Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD.)
Abstract	UNLABELLED: Wnt signaling is important for cancer pathogenesis and is often up-regulated in hepatocellular carcinoma (HCC). Heparan sulfate proteoglycans (HSPGs) function as coreceptors or modulators of Wnt activation. Glypican-3 (GPC3) is an HSPG that is highly expressed in HCC, where it can attract Wnt proteins to the cell surface and promote cell proliferation. Thus, GPC3 has emerged as a candidate therapeutic target in liver cancer. While monoclonal antibodies to GPC3 are currently being evaluated in preclinical and clinical studies, none have shown an effect on Wnt signaling. Here, we first document the expression of Wnt3a, multiple Wnt receptors, and GPC3 in several HCC cell lines, and demonstrate that GPC3 enhanced the activity of Wnt3a/ß-catenin signaling in these cells. Then we report the identification of HS20, a human monoclonal antibody against GPC3, which preferentially recognized the heparan sulfate chains of GPC3, both the sulfated and nonsulfated portions. HS20 disrupted the interaction of Wnt3a and GPC3 and blocked Wnt3a/ß-catenin signaling. Moreover, HS20 inhibited Wnt3a-dependent cell proliferation in vitro and HCC xenograft growth in nude mice. In addition, HS20 had no detectable undesired toxicity in mice. Taken together, our results show that a monoclonal antibody primarily targeting the heparin sulfate chains of GPC3 inhibited Wnt/ß-catenin signaling in HCC cells and had potent antitumor activity in vivo. CONCLUSION: An antibody directed against the heparan sulfate of a proteoglycan shows efficacy in blocking Wnt signaling and HCC growth, suggesting a novel strategy for liver cancer therapy.
File Format	HTM / HTML
ISSN	02709139
e-ISSN	15273350
DOI	10.1002/hep.26996
Journal	Hepatology
Issue Number	2
Volume Number	60
Language	English
Publisher	Wiley
Publisher Date	2014-08-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Discipline Hepatology Antibodies, Monoclonal Immunology Carcinoma, Hepatocellular Glypicans Heparitin Sulfate Liver Neoplasms Wnt Signaling Pathway Animals Pharmacology Drug Therapy Cell Surface Display Techniques Hep G2 Cells Mice Mice, Inbred Balb C Mice, Nude Drug Effects Xenograft Model Antitumor Assays Beta Catenin Research Support, N.i.h., Intramural
Content Type	Text
Resource Type	Article
Subject	Hepatology

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