Liver Cancer Biomarkers
What is hepatocellular carcinoma?
Hepatocellular carcinoma (HCC) is the third most common cause of cancer related death worldwide, and it is a major cause of death in patients with cirrhosis. The incidence of HCC has been increasing in the last 40 years, and the associated mortality is still increasing in the United States and Canada. Neoplasm formation in the liver is generally detected through ultrasonography, magnetic resonance imaging (MRI) or an abdominal computerized tomography (CT) scan. While these methods are accurate in the detection of HCC, they often fail to discover tumor formations until the later stages, which is also the main reason for the low survival rate of liver cancer. Therefore, early detection of tumors is very important for the treatment of tumors, and the use of biomarkers has greatly advanced early cancer detection, which generates better survival rates.
Figure 1. Global incidence of hepatocellular carcinoma. Sourced from GLOBOCAN 2012.
Types of hepatocellular carcinoma
Hepatocellular carcinoma (HCC) is a major killer among the malignant liver tumors and can be divided into two types: primary HCC and secondary HCC. Primary hepatocellular carcinoma (PHC) originates from either the epithelium or mesenchymal tissue of the liver and has a high incidence in China compared to second hepatocellular carcinoma (SHC). SHC refers to the invasion of the liver by malignant tumors originating different organs throughout the body. In general, it most commonly induced the liver metastases from malignant tumors of the stomach, biliary tract, pancreas, colon and rectum, ovary, uterus, lung, breast, and so on.
Risk factors for hepatocellular carcinoma
Risk factors leading to hepatocellular carcinogenesis include regional and age differences, hepatitis virus, aflatoxin, chemicals, cirrhosis and family inheritance. Most of the burden of liver cancer is in developing countries, where almost 85% of the cases occur. Most cases of HCC are associated with chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infections, which contributes up to 85% of HCC cases worldwide, The frequency of cirrhosis among patients with HCC has been shown to be 85%-95%, and the HCC incidence rate among cirrhotic patients has been estimated to be 2%-4% per year.
Hepatocellular carcinoma proteins
Biomarkers are physiological, biochemical, immunological, and genetic changes in organs at the cellular and subcellular levels caused by a variety of organic and microenvironmental factors. Tumor biomarker is a set of substances produced and released by cancer cells, often existing in tumor cells or host body fluids in the form of antigens, enzymes, hormones, and other metabolites. These markers can help in tumor identification or diagnosis by assessing the change in their concentration within the body fluids, excretions, and tissues of cancer patients according to their biochemical or immunological characteristics. They can be roughly divided into two categories: secretion of cancer cells and expression in cancer cells. We elaborately classified the series of biomarker related to the HCC into five types according to their characteristics and existence.
Table 1. Biomarker related to the hepatocellular carcinoma
| Types | Reported marker |
| Protein tumor markers | AFP, GP73, AFP-L3, GPC-3, HSP27, OPN, SF, CD166 |
| Cytokines | TGFβ1, IGF-II, HGF, TSGF |
| Enzyme markers | DCP, AFU, serum GGT, MMP |
| Antibodies and antigens | SCCA, CEA, CA19-9, CA12-5, CA50, CA15-3 |
| Cell markers | microRNAs, CTC, HCCR, AFP-mRNA, P53, SALL4, CDH17 |
AFP: Alpha-fetoprotein; GP73:Golgi ransmembrane glycoprotein73; AFP-L3: Alpha-fetoprotein heterogenous; GPC-3: Phosphatidylinositol proteoglycan-3; HSP27: Heat shock protein 27; OPN: Osteopontin; SF: Serum ferritin; CD166: Cluster of differentiation 166; TGFβ1: Transforming growth factor-beta 1; IGF-II: Insulin-like growth factor 2; HGF: Hepatocyte growth factor; TSGF: Tumor-specific growth factor; DCP: Des-gamma-carboxy prothrombin; AFU: Alpha-L-fucosidase; GGT: Glutamyl transpeptidase; MMP: Matrix metalloproteinase; SCCA: Squamous cell carcinoma antigen; CEA: Carcinoembryonic antigen; CA: Cancer antigen; MicroRNAs: Microribonucleic acids; CTC: Cyclic tumor cell; HCCR: Human cervical cancer gene; SALL4: Sal-like protein 4; CDH17: Cadherin-17.
Protein biomarkers of hepatocellular carcinoma
Alpha-fetoprotein and alpha-fetoprotein-L3
It is a glycoprotein which belongs to the albumin family and is mainly synthesized by fetal hepatocytes and yolk sacs. It has a high concentration in fetal blood, but it decreases after birth: albumin replaces alpha-fetoprotein (AFP) in 2-3 months after birth. It is difficult to detect AFP in adults, for its content in adult serum is very low. AFP-L3 is derived from cancerous hepatocytes and has high specificity for HCC. The content of AFP-L3 is related to portal vein invasion, tumor differentiation, and malignant features of PHC and prognosis of PHC.
GP73
GP73 is an ideal serum marker for early diagnosis and evaluation of recurrence of HCC. Its sensitivity and specificity are much higher than AFP. It is a more sensitive marker of liver injury, and an early warning of HCC. It's level is closely related to the severity of liver injury.
Phosphatidylinositol proteoglycan-3
Phosphatidylinositol proteoglycan-3 (GPC-3) plays an important role in the progress of PHC. The expression of GPC-3 is progressively increased during malignant transformation of hepatocytes.
Heat shock protein 27
Heat shock protein 27 (Hsp27), also known as heat shock protein beta-1, is a human protein that is encoded by the HSPB1 gene.
Osteopontin
Senger et al. reported for the first time in 1979 that a phosphorylated glycoprotein containing RGD integrin-binding region related to malignant transformation was associated with tumors, which was called transformation-related phosphoprotein.
Serum ferritin
Serum ferritin (SF) is one of the main forms of iron stored in human body. Radioimmunoassay and enzyme-linked immunosorbent assay are currently used for its detection.
Des-γ-carboxy prothrombin
Des-γ-carboxy prothrombin (DCP) referred to as abnormal prothrombin is a protein induced by deficiency of Vitamin K or antagonist-II, also known as PIVKA-II, which can appear in the serum of patients with Vitamin K deficiency or HCC.
Alpha-L-fucosidase
Alpha-L-fucosidase (AFU) is a lysosomal acid hydrolase. It is of great value in the diagnosis of AFP-negative cases and small-cell HCC and is useful in the diagnosis of early primary HCC.
Serum gamma-glutamyltransferase
Gamma-glutamyltransferase (GGT) is primarily present in kidney, liver, and pancreatic cells. Even though renal tissue has the highest level of GGT, the enzyme present in the serum appears to originate primarily from the hepatobiliary system. GGT activity is elevated in all forms of liver disease.
Matrix metalloproteinases
Matrix metalloproteinases (MMPs) are a large family of enzymes that need Ca2+, Zn2+, and other metal ions as cofactors. The MMPs share a common domain structure. The three common domains are the pro-peptide, the catalytic domain, and the hemopexin-like C-terminal domain, which are linked to the catalytic domain by a flexible hinge region.
MMPs can degrade almost all kinds of protein components in extracellular matrix, destroy the histological barrier of tumor cell invasion, and play a key role in the invasion and metastasis of tumors. Therefore, the role of MMPs in the invasion and metastasis of tumors has been paid more and more attention.
Squamous cell carcinoma antigen (SCCA)
The squamous cell carcinoma antigen is a tumor associated protein belonging to a family of high molecular weight serine protease inhibitors. SCCA has been isolated into two isoforms: SCCA1 and SCCA2. Both isoforms are expressed in a layer of the squamous epithelium and overexpression has been associated with tumorigenesis. There is a strong association with the presence of SCCA in many different forms of cancer, including HCC, leading various groups to investigate its viability as a potential biomarker.
References:
1. Zacharakis G, Aleid A, Aldossari K K. New and old biomarkers of hepatocellular carcinoma[J]. Hepatoma Res, 2018, 4: 65.
2. Du Q, Ji X, Yin G, et al. Research advancement in the tumor biomarker of hepatocellular carcinoma[J]. Cancer Translational Medicine, 2018, 4(6): 153.
3. Kim J U, Shariff M I F, Crossey M M E, et al. Hepatocellular carcinoma: Review of disease and tumor biomarkers[J]. World journal of hepatology, 2016, 8(10): 471.
