Cell Surface Proteins in Hepatocellular Carcinoma: From Bench to Bedside

Abstract

Cell surface proteins act as the go-between in carrying the information from the extracellular environment to the intracellular signaling proteins. However, these proteins are often deregulated in neoplastic diseases, including hepatocellular carcinoma. This review discusses several recent studies that have investigated the role of cell surface proteins in the occurrence and progression of HCC, highlighting the possibility to use them as biomarkers of the disease and/or targets for vaccines and therapeutics.

Hyaluronated and PEGylated Liposomes as a Potential Drug-Delivery Strategy to Specifically Target Liver Cancer and Inflammatory Cells

“…In fact, the analysis of CD44 transcript levels in these two liver cancer cell lines showed an aberrant expression of CD44 in Huh7, in comparison with HepG2 cells in which the CD44 receptor was almost absent, suggesting that CD44 expression progressively increases during the acquisition of a more aggressive phenotype. Our data are consistent with the following literature data: (i) Siracusano and colleagues [ 22 ] reported a crucial role for CD44 in maintaining the cancer stemness of Huh7; (ii) CD44 expression was observed to increase in HCC progenitor cells (HcPCs) during cancer progression [ 30 ]; (iii) CD44 is necessary for the EMT process in HCC cell lines and is associated with the mesenchymal phenotype [ 31 ].…”

“…As previous studies have reported the use of modified liposomes as a satisfactory and efficient technique for delivering drugs to liver cancer cells as they can elude the delivery restrictions implemented by the reticuloendothelial system (RES) after systemic administration [ 22 ], we decided to evaluate the effect of HA, which is ligand of the CD44 receptor, on the cellular uptake of liposomes. For this purpose, we prepared the following liposome formulations: (a) non-decorated liposomes (ND); (b) liposomes decorated with HA at a molecular weight of 4800 (HA 4800); and (c) liposomes decorated with HA at a molecular weight of 17000 (HA 17000).…”

“…A large amount of research [ 11 ] has been carried out on various receptors to improve drug-delivery carrier systems, and these include the following: (i) lactosylated liposomes that encapsulate calcein/doxorubicin; (ii) RGD (arginine-glycine-aspartate)-coupled liposomes to target integrin receptors in HCC; (iii) liposomes coated with folic acid to improve targeting ability towards the folate receptor; and (iv) glycyrrhetinic acid (GA)-modified liposomes that are a potential target for drug delivery in HCC as they exploit GA-receptor overexpression on the hepatocyte surface [ 22 ].…”

“…Along these lines, the cluster of differentiation 44 (CD44) antigen is a cell-surface glycoprotein receptor that can modulate several biological functions, including hematopoiesis, lymphocyte activation, recirculation, and homing, as well as tumor progression and metastasis. This transmembrane glycoprotein is a receptor for hyaluronic acid (HA), but also binds osteopontin, collagen, and fibronectin, as well as acting as a co-receptor for epidermal growth factor receptor (EGFR) and c-Met [ 22 , 23 ]. In addition, through its interaction with HA, CD44 is involved in monocyte differentiation as well as in several macrophage-mediated functions, such as adhesion to extracellular matrix, phagocytosis, chemotaxis to inflammatory sites, and the secretion of cytokines [ 24 ].…”

“…CD44 has been introduced as a cancer stem cells marker in HCC together with CD90, CD133, CD24, and EpCAM, and is reported to be involved in tumor initiation and growth, cancer progression, and promoting metastasis [ 22 , 23 ]. Moreover, literature meta-analysis data show that CD44 is associated with tumor stage (evaluated with the Classification of Malignant Tumors, TNM) and has been suggested to be an independent factor in reduced overall survival, with its expression correlating with worse prognosis in HCC patients [ 22 , 23 ].…”