Glypican‐3: A promising biomarker for hepatocellular carcinoma diagnosis and treatment

Abstract

Liver cancer is the second leading cause of cancer-related deaths, and hepatocellular carcinoma (HCC) is the most common type. Therefore, molecular targets are urgently required for the early detection of HCC and the development of novel therapeutic approaches. Glypican-3 (GPC3), an oncofetal proteoglycan anchored to the cell membrane, is normally detected in the fetal liver but not in the healthy adult liver. However, in HCC patients, GPC3 is overexpressed at both the gene and protein levels, and its expression predicts a poor prognosis. Mechanistic studies have revealed that GPC3 functions in HCC progression by binding to molecules such as Wnt signaling proteins and growth factors. Moreover, GPC3 has been used as a target for molecular imaging and therapeutic intervention in HCC. To date, GPC3-targeted magnetic resonance imaging, positron emission tomography, and near-infrared imaging have been investigated for early HCC detection, and various immunotherapeutic protocols targeting GPC3 have been developed, including the use of humanized anti-GPC3 cytotoxic antibodies, treatment with peptide/DNA vaccines, immunotoxin therapies, and genetic therapies. In this review, we summarize the current knowledge regarding the structure, function, and biology of GPC3 with a focus on its clinical potential as a diagnostic molecule and a therapeutic target in HCC immunotherapy.

<p>Nanocarrier-Based Therapeutics and Theranostics Drug Delivery Systems for Next Generation of Liver Cancer Nanodrug Modalities</p>

“…For example, HCC cell has asialoglycoprotein (ASGP) receptor where ligands from nanocarrier like galactoside, galactosamine, lactose, sterylglucoside, pullulan, lactobionic acid complementarily bind to ASGP receptor. 95 Bioactive moieties such as chemotherapeutic drug or specific gene will be released into the liver cancer specific site after the nanocarriers bind to the surface. Figure 7 shows the active targeting strategies of nanocarrier for liver.…”

“…Glypican-3A is recently reported as a promising biomarker for hepatocellular carcinoma. 95 In active targeting, scientists developed different gene silencing technologies such as antisense technologies, small activating RNAs (saRNAs) for liver tumor targeting. The development of a saRNAs upregulates the enhancer binding protein α (CEBPA).…”

HCC Immune Surveillance and Antiviral Therapy of Hepatitis C Virus Infection

“…Third, this study focused on only GPC-3-specific T cell responses and thus may not reflect the entirety of the immune surveillance machinery of HCC. Although we reckon that GPC-3 is the best TAA for studies like this one because of its high immunogenicity [12] and for it being the center of attention for the recent advances in HCC immunotherapy and adoptive T-cell therapy [30,29,[38][39][40][41], investigation of other TAAs should be considered in future studies. In summary, our study here demonstrated that HCC-specific T cell responses are readily detectable in patients with liver cirrhosis relative to non-cirrhotic controls.…”

“…HLA-A*0201-restricted HCC-specific peptides of AFP [137][138][139][140][141][142][143][144][145] (PLFQVPEPV), NY-ESO-1 157-165 (SLLMWITQC), MAGE-A3 112-120 (KVAELVHFL), MAGE-A10 [254][255][256][257][258][259][260][261][262] (GLYDGMEHL), SSX-2 [41][42][43][44][45][46][47][48][49] (KASEKIFYV) and p53 [149][150][151][152][153][154][155][156][157] (STPPPGTRV) at purities ranging from 82.78 to 97.99% were also obtained from ProImmune Ltd. For these HCC-associated epitope-specific peptides, corresponding PE-labeled MHC class I dextramers were obtained from Immudex (Copenhagen, Denmark). Further, HBV-specific 15-mer overlapping peptides covering the core (4 pools from 41 peptides) and polymerase regions (8 pools from 165 peptides) were purchased from ProImmune Ltd. Also, HLA-A*0201-restricted HBV-specific peptides Core [18][19][20][21][22][23][24][25][26][27] (FLPSDFFPSV), Env [183][184][185][186][187][188]<...>…”

Tumor Microenvironment: Extracellular Matrix Alterations Influence Tumor Progression

“…Glypican-3 is an important player in the Wnt, Hedgehog, and YAP signaling cascades involved in cancer cell proliferation and migration (108,109). It is overexpressed in hepatocarcinoma and lung carcinoma and was reported as a poor prognosis marker in hepatocarcinoma.…”