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The role of glypican-3 in regulating Wnt in hepatocellular carcinomas.

ABSTRACT: Glypican-3 (GPC3) is highly expressed in human hepatocellular carcinoma (HCC) and a growing body of evidence supports the role of GPC3 in HCC pathogenesis. In this review, we discuss recent developments regarding the regulation of GPC3 in HCC and provide insight about GPC3 as a potential therapeutic target in liver cancer. One of the most well studied pathways related to the biological functions of GPC3 is the Wnt signaling pathway. GPC3 may form a complex with Wnt and stimulates HCC growth. GPC3 does this by facilitating and/or stabilizing the interaction between Wnt and Frizzled, leading to the activation of downstream signaling pathways. This signaling complex is also affected by Sulfatase 2 (SULF2), a heparin-degrading endosulfatase. Removing the sulfate groups from GPC3 enhances Wnt signaling and HCC proliferation suggesting that GPC3, Wnts and SULF2 may be part of "a glypican-Wnt/growth factor complex", which may determine cell growth, differentiation and migration. Given the high expression of GPC3 in HCC, GPC3 has been suggested as a potential target for antibody-based therapy for liver cancer. A monoclonal antibody (GC33) is being evaluated in clinical studies as a single agent or in combination with Sorafenib to treat patients with advanced or metastatic HCC. Ongoing clinical trials will help define the utility of GPC3 as a novel target for liver cancer therapy.

SUBMITTER: Gao W

PROVIDER: S-EPMC3343874 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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The role of glypican-3 in regulating Wnt in hepatocellular carcinomas.

Gao Wei W Ho Mitchell M

Cancer reports 20110101 1

Glypican-3 (GPC3) is highly expressed in human hepatocellular carcinoma (HCC) and a growing body of evidence supports the role of GPC3 in HCC pathogenesis. In this review, we discuss recent developments regarding the regulation of GPC3 in HCC and provide insight about GPC3 as a potential therapeutic target in liver cancer. One of the most well studied pathways related to the biological functions of GPC3 is the Wnt signaling pathway. GPC3 may form a complex with Wnt and stimulates HCC growth. GPC ...[more]

PMID: 22563565

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Project description:Background and aimsGlypican 3 (GPC3) is an oncofetal antigen involved in Wnt-dependent cell proliferation that is highly expressed in hepatocellular carcinoma (HCC). We investigated whether the functions of chimeric antigen receptors (CARs) that target GPC3 are affected by their antibody-binding properties.MethodsWe collected peripheral blood mononuclear cells from healthy donors and patients with HCC and used them to create CAR T cells, based on the humanized YP7 (hYP7) and HN3 antibodies, which have high affinities for the C-lobe and N-lobe of GPC3, respectively. NOD/SCID/IL-2Rgcnull (NSG) mice were given intraperitoneal injections of luciferase-expressing (Luc) Hep3B or HepG2 cells and after xenograft tumors formed, mice were given injections of saline or untransduced T cells (mock control), or CAR (HN3) T cells or CAR (hYP7) T cells. In other NOD/SCID/IL-2Rgcnull (NSG) mice, HepG2-Luc or Hep3B-Luc cells were injected into liver, and after orthotopic tumors formed, mice were given 1 injection of CAR (hYP7) T cells or CD19 CAR T cells (control). We developed droplet digital polymerase chain reaction and genome sequencing methods to analyze persistent CAR T cells in mice.ResultsInjections of CAR (hYP7) T cells eliminated tumors in 66% of mice by week 3, whereas CAR (HN3) T cells did not reduce tumor burden. Mice given CAR (hYP7) T cells remained tumor free after re-challenge with additional Hep3B cells. The CAR T cells induced perforin- and granzyme-mediated apoptosis and reduced levels of active β-catenin in HCC cells. Mice injected with CAR (hYP7) T cells had persistent expansion of T cells and subsets of polyfunctional CAR T cells via antigen-induced selection. These T cells were observed in the tumor microenvironment and spleen for up to 7 weeks after CAR T-cell administration. Integration sites in pre-infusion CAR (HN3) and CAR (hYP7) T cells were randomly distributed, whereas integration into NUPL1 was detected in 3.9% of CAR (hYP7) T cells 5 weeks after injection into tumor-bearing mice and 18.1% of CAR (hYP7) T cells at week 7. There was no common site of integration in CAR (HN3) or CD19 CAR T cells from tumor-bearing mice.ConclusionsIn mice with xenograft or orthoptic liver tumors, CAR (hYP7) T cells eliminate GPC3-positive HCC cells, possibly by inducing perforin- and granzyme-mediated apoptosis or reducing Wnt signaling in tumor cells. GPC3-targeted CAR T cells might be developed for treatment of patients with HCC.

Dataset Information

The role of glypican-3 in regulating Wnt in hepatocellular carcinomas.

Publications

The role of glypican-3 in regulating Wnt in hepatocellular carcinomas.

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