Liver Angiopoietin‐2 Is a Key Predictor of D e N ovo or Recurrent Hepatocellular Cancer After Hepatitis C Virus Direct‐Acting Antivirals

Abstract

Recent reports suggested that direct acting antivirals (DAAs) might favor hepatocellular carcinoma (HCC). In study 1, we studied the proangiogenic liver microenvironment in 242 DAA‐treated chronic hepatitis C patients with advanced fibrosis. Angiopoietin‐2 (ANGPT2) expression was studied in tissue (cirrhotic and/or neoplastic) from recurrent, de novo, nonrecurrent HCC, or patients never developing HCC. Circulating ANGPT2,vascular endothelial growth factor (VEGF), and C‐reactive protein (CRP) were also measured. In study 2, we searched for factors associated with de novo HCC in 257 patients with cirrhosis of different etiologies enrolled in a dedicated prospective study. Thorough biochemical, clinical, hemodynamic, endoscopic, elastographic, and echo‐Doppler work‐up was performed in both studies. In study 1, no patients without cirrhosis developed HCC. Of 183 patients with cirrhosis, 14 of 28 (50.0%) with previous HCC recurred whereas 21 of 155 (13.5%) developed de novo HCC. Patients with recurrent and de novo HCCs had significantly higher liver fibrosis (LF) scores, portal pressure, and systemic inflammation than nonrecurrent HCC or patients never developing HCC. In recurrent/de novo HCC patients, tumor and nontumor ANGPT2 showed an inverse relationship with portal vein velocity (PVv; r = –0.412, P = 0.037 and r = –0.409, P = 0.047 respectively) and a positive relationship with liver stiffness (r = 0.526, P = 0.007; r = 0.525, P = 0.003 respectively). Baseline circulating VEGF and cirrhotic liver ANGPT2 were significantly related (r = 0.414, P = 0.044). VEGF increased during DAAs, remaining stably elevated at 3‐month follow‐up, when it significantly related with serum ANGPT2 (r = 0.531, P = 0.005). ANGPT2 expression in the primary tumor or in cirrhotic tissue before DAAs was independently related with risk of HCC recurrence (odds ratio [OR], 1.137; 95% confidence interval [CI], 1.044‐1.137; P = 0.003) or occurrence (OR, 1.604; 95% CI, 1.080‐2.382; P = 0.019). In study 2, DAA treatment (OR, 4.770; 95% CI, 1.395‐16.316; P = 0.013) and large varices (OR, 3.857; 95% CI, 1.127‐13.203; P = 0.032) were independent predictors of de novo HCC. Conclusion: Our study indicates that DAA‐mediated increase of VEGF favors HCC recurrence/occurrence in susceptible patients, that is, those with more severe fibrosis and splanchnic collateralization, who already have abnormal activation in liver tissues of neo‐angiogenetic pathways, as shown by increased ANGPT2. (Hepatology 2018; 00:000‐000).

Virological and Clinical Outcome of DAA Containing Regimens in a Cohort of Patients in Calabria Region (Southern Italy)

“…All these characteristics (advanced age, comorbidities, and high burden of comedications) could potentially affect tolerability of HCV treatment and adherence in this subgroup [7]. Moreover, some possible side effects and biomarker alterations, as well as increased risk of liver cancer, have been reported by several authors, especially in elderly people [8][9][10][11][12][13]. In addition, the presence of some side effects was in particular reported among those who had concurrent comorbidities (such as liver cirrhosis, cardiac failure, and advanced age) [14,15].…”

Vessels Encapsulating Tumor Clusters (VETC) Is a Powerful Predictor of Aggressive Hepatocellular Carcinoma

“…Interestingly, a signature of five genes (angiopoietin‐2 [ ANGPT2 ], delta‐like ligand 4 [ DLL4 ], neuropilin/tolloid‐like 2 [ NETO2 ], endothelial cell‐specific molecule‐1 [ ESM1 ], and nuclear receptor subfamily 4, group A, member 1 [ NR4A1 ]), all related to angiogenesis, characterized a subset of highly aggressive and fast‐growing HCC at onset . It is therefore likely that vascular pattern heterogeneity can also play a role in tumor progression . Interestingly, Fang et al reported a distinct pattern of HCC vascularization that predicted rapid tumor dissemination and high recurrence rates .…”

“…(9) It is therefore likely that vascular pattern heterogeneity can also play a role in tumor progression. (10) Interestingly, Fang et al reported a distinct pattern of HCC vascularization that predicted rapid tumor dissemination and high recurrence rates. (11) This pattern is characterized by the presence of CD34 + vessels completely encapsulating tumor clusters (VETC).…”

<p>Hepatocellular Carcinoma Mechanisms Associated with Chronic HCV Infection and the Impact of Direct-Acting Antiviral Treatment</p>

“…They also showed that angiopoietin-2 expression in HCC and cirrhotic tissue before DAAs treatment relates to the risk of HCC recurrence and occurrence. 331 Recently, we reported that HCC developed in the cirrhotic liver when the hepatic adaptive response reprogrammed to switch from prodeath to the pro-survival state through autophagy switching. In addition, our laboratory illustrated that virus-associated ER stress and tumor suppressor loss (p53 and Rb, miR-122 levels) were restored more by IFN-induced HCV clearance than DAAs in cell culture models.…”