Extracellular Glycosaminoglycans in Management of Primary Hepatocellular Carcinoma Rather than Alpha Fetoprotein

Research Article

J Dis Markers. 2016; 3(1): 1036.

Extracellular Glycosaminoglycans in Management of Primary Hepatocellular Carcinoma Rather than Alpha Fetoprotein

Abdel-Hamid NM¹*, Abdel-Fattah SM², Nazmy MH³ and Mahmoud AS³

¹Biochemistry Department, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt

²National Cancer Institute, Cairo University, Cairo, Egypt

³Biochemistry Department, Faculty of Pharmacy, Minia University, Minia, Egypt

*Corresponding author: Nabil Mohie Abdel-Hamid, Ex-Dean of College of Pharmacy, Kafrelsheikh University, Egypt

Received: February 16, 2016; Accepted: March 17, 2016; Published: March 21, 2016


Objectives: Extracellular matrix (ECM) is an essential player at various stages of carcinogenesis. Current study aims to evaluate diagnostic value of components of ECM, released to the serum, i.e. total glycosaminoglycans (TGAGs), total sialic acid (TSA) and free glucosamine (FGA) in primary HCC patients solely or confounded by other conditions (i.e. diabetes mellitus (DM), hepatitis C virus (HCV) or bilharziasis (B).

Design and Methods: Our study was conducted upon 40 HCC patients: 32 (80%) males, 8 (20%) females, among these samples, patients with ascites, single/or multiple HCC lesions, as shown in demographic Table.

Results: Liver and renal indices were significantly disturbed in HCC patients. Significant elevations of AFP, TGAGS and FGA, non-significant increases in TSA in HCC patients compared to normal control. These parameters except AFP showed significant persistent higher levels during cancer progression. AFP showed irrelevant changes to the stages of HCC lesion. HCC patients with HCV, DM or B showed significantly higher levels of AFP than with HCC solely. Both TGAGs and FGA showed the highest diagnostic accuracy over AFP, but TSA showed the lowest value.

Conclusion: TGAGs and FGA may be regarded as cost-effective and more accurate diagnostic tools during primary HCC progression, whether solely, or commixed by other diseases.

Keywords: Hepatocellular carcinoma (HCC); Alpha-fetoprotein; Glycosaminoglycans (TGAGs); Total sialic acid (TSA); Free glucosamine (FGA)


AFP: Alpha Fetoprotein; ECM: Extracellular Matrix; FGA: Free Glucosamine; FSA: Free Sialic Acid; HCC: Hepatocellular Carcinoma; TGAGs: Total Glycosaminoglycans; TSA: Total Sialic Acid


Hepatocellular carcinoma (HCC) is a multistage disease not only because different molecular aetiologies underlie the same clinical outcome, but also, variable cell types, in addition to cancer cells, and non-cellular components need to play together to support the survival, growth and invasion of cancer [1]. Extracellular matrix (ECM), a major component of the local microenvironment, was considered as an principal factor at various stages of the carcinogenesis. Its functional diversity and dynamic nature, allows the ECM to participate in cell behaviour and developmental processes, whose disruption may be a critical step in cancer management [2]. The ECM is composed of proteins, glycoproteins, proteoglycans and polysaccharides with different physical and biochemical properties [3]. These components make up basement membrane, which is expressed by epithelial, endothelial and stromal cells to separate epithelium or endothelium from stroma and interstitial matrix, which is primarily made by stromal cells [4].

Proteoglycans possess a protein core to which glycosaminoglycan (GAG) chains are covalently linked [5]. GAGs are heteropolysaccharides present in all mammalian tissue, consisted of repeating disaccharide units with either sulphated or non-sulphated monosaccharides [6]. Recently, GAGs were counted among key macromolecules that affect cell properties and functions, acting directly on cell receptors or via interactions with growth factors. Altered structure of GAGs was observed in several diseases, announcing for their importance for disease diagnosis and progression, as well as pharmacological targets. Structural characteristics of GAGs and enzymes involved in their biosynthesis and degradation, are involved in cell signalling, cell function and cancer progression [7,8].

Sialic acid (SA), an important component of nine carbon atom ketoses, is an acetylated derivative of neuraminic acid (2-keto-5- amino-3, 5-dideoxy-D-nonulosonic acid) [9,10]. In addition, its negative charge due to a carboxyl group, contributes to the biophysical features of several biological roles, such as cell-to-cell recognition and transformation to malignancy [11]. D-Glucosamine (2-amino- 2-deoxy-D-glucose) is an amino monosaccharide component of glycoproteins, glycolipids and GAGs [12]. It is synthesized in the phosphorylated form, glucosamine-6-phosphate from fructose-6- phosphate and glutamine by glucosamine fructose-6-phosphate amidotransferase, which is the first and rate-limiting step of the hexosamine biosynthetic pathway. In humans, the endogenous production of glucosamine is in ranges from 4 to 20 g/day [13]. Exogenous glucosamine is actively transported into the animal cells by glucose transporters, phosphorylated to glucosamine-6-P by hexokinase. Glucosamine-6-P is converted either back to fructose- 6-P by deamination for glycolysis pathway [14], or to UDP-N-acetyl glucosamine which serves as a donor of N-acetyl-glucosamine for Oor N-linked protein glycosylation [15].

The current study aims to re-examine possible disruptions in certain individual components of ECM (i.e. total glycosaminoglycans (TGAGs), total sialic acid (TSA) and free glucosamine (FGA), and to evaluate their possible diagnostic value in primary HCC patients, as , we previously studied these figures at an experimental level.

Patients and Methods

Sixty patients were recruited from Minia oncology institute through September 2013 to April 2014. All patients were fully aware of the purpose of the study and signed a written consent. The study protocol was approved by the Ethics Committee of the Faculty of Pharmacy, Minia University, Egypt, in accordance with the Helsinki Declaration of 1975. Twenty age and sex matched apparently healthy subjects were taken as controls. This study included 40 patients with histologically proven primary HCC aged 28 to 62 years (32 males and 8 females). All studied patients and controls were subjected to the following investigations:

Medical and demographic data and abdominal ultrasonography (US). Other co-morbid diseases such as diabetes mellitus, HCV and bilharziasis. Complete clinical and general examination. Laboratory investigations, serum albumin, AST, and ALT, blood urea, creatinine, hepatitis C virus antibodies (anti-HCV) and proposed markers: AFP, TGAGs, FGA and TSA.

General characteristics of study population

The study included 40 HCC patients: 32(80%) males and 8(20%) females, separately, 10 with ascites, 17 had single HCC lesion, 8 had two HCC lesions and 15 had multiple lesions. HCV antibodies were detected in 25 of HCC cases, 5 had DM while 14 had urinary bilharziasis (Table 1).