A Comparative Study of Serum Angiogenic Biomarkers in Cirrhosis and Hepatocellular Carcinoma

Abstract

Background: Hepatocellular carcinoma (HCC) is a global health problem associated with chronic liver disease. Its pathogenesis varies according to the underlying etiological factors, although in most cases it develops from liver cirrhosis. The disease progression is accompanied by pathological angiogenesis, which is a prerequisite that favors the development of HCC. Aims: This study aims at contributing to our understanding of the role of angiogenic factors in the progression of liver disease. For this purpose, we evaluate the clinical significance of serum angiogenic markers (VEGF, Ang-1, Ang-2, the angiopoietin receptor Tie1/2, HGF, and PECAM-1) first in cirrhotic and HCC patients separately, and then comparing cirrhotic patients with and without HCC. Materials and Methods: We enrolled 62 patients, out of whom 33 were diagnosed with HCC and 29 with liver cirrhosis without signs of neoplasia. Patients underwent venous blood sampling before and after receiving treatments for the diagnosed disease. Serum markers were evaluated using ELISA assays for Tie1 and the Bio-Plex Multiplex system for the remaining ones. Biomarker levels were investigated as a function of clinical scores for disease staging (MELD and Fibrosis Index, FI). Results: In cirrhotic patients, Ang-1 and Ang-2 correlate with MELD (ρAng-1 = −0.73, p = 2E−5) and FI (ρAng-1 = −0.52, p = 7E−3, ρAng-2 = 0.53, p = 3E−3). A reduction of Ang-2 levels (p = 0.047) and of the Ang-2/Ang-1 ratio (p = 0.031) is observed in cirrhotic patients diagnosed with viral hepatitis after antiviral treatments. In HCC patients, Ang-1 negatively correlates with FI (ρ = −0.63, p = 1E−4), and PECAM-1 positively correlates with MELD (ρ = 0.44, p = 0.01). A significant Ang-1 reduction was observed in deceased patients during the study compared to ones who survived (p = 0.01). In HCC patients, VEGF levels were increased after tumor treatment (p = 0.037). Notably, HGF levels in cirrhotic patients with HCC are significantly raised (p = 0.017) compared to that in those without HCC. Conclusions: Our results suggest that serum angiogenic markers, with emphasis on Ang-1/2, can contribute to the development of quantitative tools for liver disease staging and therapy monitoring. The comparison between cirrhotic patients with and without HCC suggests that HGF levels are potentially useful for monitoring the insurgence of HCC after a cirrhosis diagnosis. High Ang-1 levels in HCC patients appear to have a protective role as well as prognostic significance.

Machine Learning-Assisted FTIR Analysis of Circulating Extracellular Vesicles for Cancer Liquid Biopsy

“…HCC diagnosis is currently carried out by combining different types of information, which include the levels of selected circulating markers, medical imaging (US/MRI/CT), and histopathological biopsies [ 25 , 33 , 50 ]. Unfortunately, all these methods present some limitations, which negatively affect patient prognosis.…”

“…Unfortunately, all these methods present some limitations, which negatively affect patient prognosis. Circulating markers, AFP included, have usually low sensitivity and specificity, although improved performance can be obtained through the combination of multiple markers [ 25 , 26 , 27 , 29 , 33 ]. Despite a remarkable specificity, medical imaging has a poor capability of detecting small tumors, being plagued by a large number of false negatives (FNs) and, consequently, a poor sensitivity.…”

“…Despite a remarkable specificity, medical imaging has a poor capability of detecting small tumors, being plagued by a large number of false negatives (FNs) and, consequently, a poor sensitivity. Histopathological biopsies also present several problems such as their invasiveness and a large number of FNs, which are partly due to the intrinsic variability of the bioptic tissue that complicates the sampling of the suspected region [ 25 , 32 , 33 , 51 , 52 ]. EV-based liquid biopsy can contribute to overcoming some of these shortcomings, as it is non- or minimally invasive and can provide a homogeneous sampling.…”

“…All the subjects enrolled in this study have given written informed consent. We selected 20 patients with a recent diagnosis of nonviral HCC, according to EASL guidelines [ 33 ]. The exclusion criteria were as follows: history of previous treatment (i.e., hepatic resection, liver transplant, anti-angiogenic drugs, and radiofrequency); diagnosis of extra-hepatic neoplasia; HCV or HBV infection; Child-Pugh B or C; obstructive jaundice; and estimated creatinine clearance < 30 mL/min.…”

“…A wide panel of biochemical parameters was measured on the collected blood samples, including Glucose, Cholesterol, Total bilirubin, Albumin, Alanine aminotransferase (ALT), Asand partate aminotransferase (AST), Alkaline phosphatase (ALP), and Gamma-Glutamyl Transferase (GGT). Patients’ sera were collected for quantitative measurement of AFP and PIVKA-II, performed using Lumipulse ® G (Fujirebio, Tokyo, Japan), based on Chemiluminescent Enzyme [ 25 , 33 ]. Vascular invasion, portal trunk, and/or main portal branches, were diagnosed by MRI with hepato-specific contrast medium.…”