Immunotherapy is one of the strategies to boost natural defenses to fight cancer. Immuno-oncology is an artificial stimulation of the human immune system to recognize and kill selectively neoplastic cells at different stage of transformation. Cancer cells have tumor antigens and the antibody of the immune system, binding them, can detect molecules on their extracellular side of cell membrane. Among these proteins, it is rising in interest and use d for early detection of hepatocellular carcinoma (HCC) Glypican-3 (GPC-3) protein. It is a heparan sulfate proteoglycan (HSPG), anchored to the cell membrane of transformed hepatocytes. We investigated its function as key regulator of hepatocytes neoplastic transformation. Noteworthy, GPC-3 protein has been implicated in different pathways from cell growth to cell motility and migration. More recently, GPC-3 has been evaluated as a useful marker for HCC due to its increased expression in the liver during tumorigenesis and its absence in normal liver. Immunotherapy that targets GPC-3 domains and its connected proteins are currently under investigation. These new biomarkers may hold potential for the detection and treatment of HCC and other diseases in which GPC-3 may be overexpressed and/or play a crucial role. This review will summarize the current knowledge regarding the active immunotherapy developed to treat HCC and it will evaluate aspects of GPC-3 (structure and biology) as advantages and potential pitfalls for considering it as a valuable immunotherapeutic target. We also elaborated the current literature with the aim to better understand its biological interactions at a molecular and cellular level to identify alternative or combined targets , due to the existing gap in the literature surrounding GPC-3. The role GPC-3 plays in the hepatocellular carcinoma phenotype can be targeted for a novel immunotherapy strategy that can specify cell-mediated destruction of neoplastic cell that spares normal liver tissue, and it can be exploited as a new serum marker to trend for diagnosis and disease progression measurements. We believe further investigation of its functions and structure, including alternative cellular localizations, is necessary to evaluate GPC-3 as valuable target to cure this cancer .
Global Burden of Disease Liver Cancer Collaboration (2017) The Burden of Primary Liver Cancer and Underlying Etiologies from 1990 to 2015 at the Global, Regional, and National Level: Results from the Global Burden of Disease Study 2015. JAMA Oncology, 3, 1683-1691.
Forner, A., Reig, M. and Bruix, J. (2018) Hepatocellular Carcinoma. The Lancet, 391, 1301-1314. https://doi.org/10.1016/S0140-6736(18)30010-2
Degasperi, E. and Colombo, M. (2016) Distinctive Features of Hepatocellular Carcinoma in Non-Alcoholic Fatty Liver Disease. The Lancet Gastroenterology & Hepatology, 1, 156-164. https://doi.org/10.1016/S2468-1253(16)30018-8
Hartke, J., Johnson, M. and Ghabril, M. (2017) The Diagnosis and Treatment of Hepatocellular Carcinoma. Seminars in Diagnostic Pathology, 34, 153-159. https://doi.org/10.1053/j.semdp.2016.12.011
Eggert, T. and Greten, T.F. (2017) Current Standard and Future Perspectives in Non-Surgical Therapy for Hepatocellular Carcinoma. Digestion, 96, 1-4. https://doi.org/10.1159/000464282
Mokdad, A.A., Hester, C.A., Singal, A.G. and Yopp, A.C. (2017) Management of Hepatocellular in the United States. Chinese Clinical Oncology, 6, 21. https://doi.org/10.21037/cco.2017.04.04
Cheraghvandi, L., Silva, M., Cheng, C., et al. (2016) Single-Step Combined Laparoscopic Management of Hepatocellular Carcinoma with Simultaneous Radio Frequency Ablation and Trans-Arterial Embolization in Unresactable Lesions. Journal of Cancer Therapy, 7, 979-985. https://doi.org/10.4236/jct.2016.713095
Cheng, A.-L., Kang, Y.-K., Chen, Z., et al. (2009) Efficacy and Safety of Sorafenib in Patients in the Asia-Pacific Region with Advanced Hepatocellular Carcinoma: A Phase III Randomised, Double-Blind, Placebo-Controlled Trial. The Lancet Oncology, 10, 25-34. https://doi.org/10.1016/S1470-2045(08)70285-7
Harding, J.J., Dika, I. and Abou-Alfa, G.K. (2016) Immunotherapy in Hepatocellular Carcinoma: Primed to Make a Difference? Cancer, 122, 367-377. https://doi.org/10.1002/cncr.29769
Patel, S.P. and Kurzrock, R. (2015) PD-L1 Expression as a Predictive Biomarker in Cancer Immunotherapy. Molecular Cancer Therapeutics, 14, 847-856. https://doi.org/10.1158/1535-7163.MCT-14-0983
Montalbano, M., Georgiadis, J., Masterson, A.L., et al. (2017) Biology and Function of Glypican-3 as a Candidate for Early Cancerous Transformation of Hepatocytes in Hepatocellular Carcinoma (Review). Oncology Reports, 37, 1291-1300. https://doi.org/10.3892/or.2017.5387
Montalbano, M., Rastellini, C., McGuire, J.T., et al. (2018) Role of Glypican-3 in the Growth, Migration and Invasion of Primary Hepatocytes Isolated from Patients with Hepatocellular Carcinoma. Cellular Oncology, 41, 169-184. https://doi.org/10.1007/s13402-017-0364-2
Montalbano, M., Curcuru, G., Shirafkan, A., Vento, R., Rastellini, C. and Cicalese, L. (2016) Modeling of Hepatocytes Proliferation Isolated from Proximal and Distal Zones from Human Hepatocellular Carcinoma Lesion. PLoS ONE, 11, e0153613. https://doi.org/10.1371/journal.pone.0153613
Montalbano, M., Rastellini, C., Wang, X., Gorgun, T., Eltorky, M.A., Vento, R. and Cicalese, L. (2016) Transformation of Primary Human Hepatocytes in Hepatocellular Carcinoma. International Journal of Oncology, 48, 1205-1217. https://doi.org/10.3892/ijo.2015.3312
Li, L., Jin, R., Zhang, X., et al. (2012) Oncogenic Activation of Glypican-3 by c-Myc in Human Hepatocellular Carcinoma. Hepatology, 56, 1380-1390. https://doi.org/10.1002/hep.25891
Xue, Y., Mars, W.M., Bowen, W., Singhi, A.D., Stoops, J. and Michalopoulos, G.K. (2018) Hepatitis C Virus Mimics Effects of Glypican-3 on CD81 and Promotes Development of Hepatocellular Carcinomas via Activation of Hippo Pathway in Hepatocytes. The American Journal of Pathology, 188, 1469-1477. https://doi.org/10.1016/j.ajpath.2018.02.013
Akutsu, N., Yamamoto, H., Sasaki, S., et al. (2010) Association of Glypican-3 Expression with Growth Signaling Molecules in Hepatocellular Carcinoma. World Journal of Gastroenterology, 16, 8. https://doi.org/10.3748/wjg.v16.i28.3521
Wang, B., Xian, J., Zang, J., et al. (2019) Long Non-Coding RNA FENDRR Inhibits Proliferation and Invasion of Hepatocellular Carcinoma by Down-Regulating Glypican-3 Expression. Biochemical and Biophysical Research Communications, 509, 143-147. https://doi.org/10.1016/j.bbrc.2018.12.091
Bi, Y., Jiang, H., Wang, P., et al. (2017) Treatment of Hepatocellular Carcinoma with a GPC3-Targeted Bispecific T Cell Engager. Oncotarget, 8, 52866-52876. https://doi.org/10.18632/oncotarget.17905
Tahon, A.M., El-Ghanam, M.Z., Zaky, S., et al. (2018) Significance of Glypican-3 in Early Detection of Hepatocellular Carcinoma in Cirrhotic Patients. Journal of Gastrointestinal Cancer, 50, 434-441. https://doi.org/10.1007/s12029-018-0095-2
Chen, D., Li, Z., Song, Q., Qian, L., Xie, B. and Zhu, J. (2018) Clinicopathological Features and Differential Diagnosis of Hepatocellular Carcinoma in Extrahepatic Metastases. Medicine, 97, e13356. https://doi.org/10.1097/MD.0000000000013356
Zhu, A.X., Gold, P.J., El-Khoueiry, A.B., et al. (2013) First-in-Man Phase I Study of GC33, a Novel Recombinant Humanized Antibody against Glypican-3, in Patients with Advanced Hepatocellular Carcinoma. Clinical Cancer Research, 19, 920-928. https://doi.org/10.1158/1078-0432.CCR-12-2616
Phung, Y., Gao, W., Man, Y.G., Nagata, S. and Ho, M. (2012) High-Affinity Monoclonal Antibodies to Cell Surface Tumor Antigen Glypican-3 Generated through a Combination of Peptide Immunization and Flow Cytometry Screening. MAbs, 4, 592-599. https://doi.org/10.4161/mabs.20933
Wang, C., Gao, W., Feng, M., Pastan, I. and Ho, M. (2017) Construction of an Immunotoxin, HN3-mPE24, Targeting Glypican-3 for Liver Cancer Therapy. Oncotarget, 8, 32450-32460. https://doi.org/10.18632/oncotarget.10592
Gao, W., Kim, H., Feng, M., et al. (2014) Inactivation of Wnt Signaling by a Human Antibody That Recognizes the Heparan Sulfate Chains of Glypican-3 for Liver Cancer Therapy. Hepatology, 60, 576-587. https://doi.org/10.1002/hep.26996
Liu, X., Wen, J., Yi, H., et al. (2020) Split Chimeric Antigen Receptor-Modified T Cells Targeting Glypican-3 Suppress Hepatocellular Carcinoma Growth with Reduced Cytokine Release. Therapeutic Advances in Medical Oncology, 12. https://doi.org/10.1177/1758835920910347
Fleming, B.D., Urban, D.J., Hall, M.D., et al. (2019) Engineered Anti-GPC3 Immunotoxin, HN3-ABD-T20, Produces Regression in Mouse Liver Cancer Xenografts through Prolonged Serum Retention. Hepatology, 71, 1696-1711. https://doi.org/10.1002/hep.30949
Fu, Y., Urban, D.J., Nani, R.R., et al. (2019) Glypican-3-Specific Antibody Drug Conjugates Targeting Hepatocellular Carcinoma. Hepatology, 70, 563-576. https://doi.org/10.1002/hep.30326